US20040033228A1 - Formulation of human antibodies for treating TNF-alpha associated disorders - Google Patents

Formulation of human antibodies for treating TNF-alpha associated disorders Download PDF

Info

Publication number
US20040033228A1
US20040033228A1 US10/222,140 US22214002A US2004033228A1 US 20040033228 A1 US20040033228 A1 US 20040033228A1 US 22214002 A US22214002 A US 22214002A US 2004033228 A1 US2004033228 A1 US 2004033228A1
Authority
US
United States
Prior art keywords
antibody
formulation
tnfα
seq
antigen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/222,140
Inventor
Hans-Juergen Krause
Lisa Baust
Michael Dickes
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AbbVie Biotechnology Ltd
Original Assignee
Abbott Biotech Ltd Bermuda
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=31714885&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20040033228(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Abbott Biotech Ltd Bermuda filed Critical Abbott Biotech Ltd Bermuda
Priority to US10/222,140 priority Critical patent/US20040033228A1/en
Priority to MYPI20070749A priority patent/MY162068A/en
Priority to MYPI20033010A priority patent/MY153718A/en
Priority to MYPI2012001176A priority patent/MY163027A/en
Priority to TW092122123A priority patent/TWI331532B/en
Priority to ES10182610.5T priority patent/ES2636692T3/en
Priority to EP10182610.5A priority patent/EP2359856B1/en
Priority to EP10182625A priority patent/EP2363145A1/en
Priority to US10/525,292 priority patent/US8216583B2/en
Priority to PT03748439T priority patent/PT1528933E/en
Priority to AU2003267744A priority patent/AU2003267744C1/en
Priority to KR1020117007142A priority patent/KR101273568B1/en
Priority to CA2882905A priority patent/CA2882905C/en
Priority to MXPA05001841A priority patent/MXPA05001841A/en
Priority to AT03748439T priority patent/ATE555809T1/en
Priority to CA2872088A priority patent/CA2872088A1/en
Priority to CN201010613919.XA priority patent/CN102078608B/en
Priority to CN201010613946.7A priority patent/CN102049045B/en
Priority to UY27940A priority patent/UY27940A1/en
Priority to EP03748439A priority patent/EP1528933B1/en
Priority to BR0313492-0A priority patent/BR0313492A/en
Priority to PL398596A priority patent/PL218221B1/en
Priority to NZ538030A priority patent/NZ538030A/en
Priority to KR1020137022247A priority patent/KR101529583B1/en
Priority to PCT/IB2003/004502 priority patent/WO2004016286A2/en
Priority to AR20030102982A priority patent/AR040881A1/en
Priority to CA2494756A priority patent/CA2494756C/en
Priority to CA2872091A priority patent/CA2872091A1/en
Priority to EP10182598A priority patent/EP2363144A1/en
Priority to EP20100182619 priority patent/EP2361637A1/en
Priority to SI200332176T priority patent/SI1528933T1/en
Priority to PT101826105T priority patent/PT2359856T/en
Priority to KR1020127026957A priority patent/KR101367743B1/en
Priority to PE2003000831A priority patent/PE20040994A1/en
Priority to CN200910253163.XA priority patent/CN101721702B/en
Priority to DK03748439.1T priority patent/DK1528933T3/en
Priority to CA2854798A priority patent/CA2854798A1/en
Priority to CA2882931A priority patent/CA2882931C/en
Priority to CN038242729A priority patent/CN1688339B/en
Priority to JP2004528780A priority patent/JP4925582B2/en
Priority to ES03748439T priority patent/ES2387616T3/en
Priority to KR1020057002604A priority patent/KR20050067140A/en
Priority to SI200332534T priority patent/SI2359856T1/en
Priority to CA2882934A priority patent/CA2882934C/en
Priority to PL375272A priority patent/PL212934B1/en
Priority to PL406852A priority patent/PL218834B1/en
Priority to CA2882907A priority patent/CA2882907C/en
Priority to DK10182610.5T priority patent/DK2359856T3/en
Priority to CA2872089A priority patent/CA2872089C/en
Assigned to ABBOTT BIOTECHNOLOGY LTD. reassignment ABBOTT BIOTECHNOLOGY LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BAUST, LISA, DICKES, MICHAEL, KRAUSE, HANS-JUERGEN
Publication of US20040033228A1 publication Critical patent/US20040033228A1/en
Priority to ZA200501032A priority patent/ZA200501032B/en
Priority to IL166809A priority patent/IL166809A/en
Priority to HK05108068.5A priority patent/HK1074008A1/en
Priority to CL2010000603A priority patent/CL2010000603A1/en
Priority to ARP100102557A priority patent/AR077412A2/en
Priority to IL207028A priority patent/IL207028A/en
Priority to JP2011204759A priority patent/JP5608619B2/en
Priority to US13/471,820 priority patent/US8932591B2/en
Priority to CY20121100631T priority patent/CY1113353T1/en
Assigned to ABBVIE BIOTECHNOLOGY LTD. reassignment ABBVIE BIOTECHNOLOGY LTD. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: ABBOTT BIOTECHNOLOGY LTD.
Priority to JP2013235924A priority patent/JP2014074034A/en
Priority to US14/091,938 priority patent/US8795670B2/en
Priority to US14/091,661 priority patent/US8802100B2/en
Priority to US14/091,888 priority patent/US8802101B2/en
Priority to US14/147,287 priority patent/US8802102B2/en
Priority to US14/322,581 priority patent/US8911741B2/en
Priority to US14/322,565 priority patent/US8940305B2/en
Priority to US14/453,490 priority patent/US8916158B2/en
Priority to US14/453,461 priority patent/US8916157B2/en
Priority to US14/558,182 priority patent/US9114166B2/en
Priority to JP2015099796A priority patent/JP2015199741A/en
Priority to US14/799,211 priority patent/US9220781B2/en
Priority to US14/826,357 priority patent/US9327032B2/en
Priority to US14/826,367 priority patent/US9272041B2/en
Priority to US14/826,377 priority patent/US9295725B2/en
Priority to US14/826,393 priority patent/US9289497B2/en
Priority to US14/826,383 priority patent/US9272042B2/en
Priority to US14/884,279 priority patent/US9302011B2/en
Priority to US15/095,393 priority patent/US9950066B2/en
Priority to US15/418,460 priority patent/US9750808B2/en
Priority to US15/418,465 priority patent/US9732152B2/en
Priority to US15/418,469 priority patent/US9738714B2/en
Priority to JP2017074982A priority patent/JP2017165736A/en
Priority to CY20171100527T priority patent/CY1118991T1/en
Priority to US15/918,663 priority patent/US20190054171A1/en
Priority to US16/057,217 priority patent/US20180339046A1/en
Priority to US17/126,500 priority patent/US20210113694A1/en
Priority to US17/472,004 priority patent/US20220241415A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39591—Stabilisation, fragmentation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/241—Tumor Necrosis Factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Tumor necrosis factor ⁇ is a cytokine produced by numerous cell types, including monocytes and macrophages, that was originally identified based on its capacity to induce the necrosis of certain mouse tumors (see e.g., Old, L. (1985) Science 230:630-632). Subsequently, a factor termed cachectin, associated with cachexia, was shown to be the same molecule as TNF ⁇ . TNF ⁇ has been implicated in mediating shock (see e.g., Beutler, B. and Cerami, A. (1988) Annu. Rev. Biochem. 57:505-518; Beutler, B. and Cerami, A. (1989) Annu. Rev. Immunol.
  • TNF ⁇ has been implicated in the pathophysiology of a variety of other human diseases and disorders, including sepsis, infections, autoimmune diseases, transplant rejection and graft-versus-host disease (see e.g., Moeller, A., et al. (1990) Cytokine 2:162-169; U.S. Pat. No. 5,231,024 to Moeller et al.; European Patent Publication No. 260 610 B1 by Moeller, A., et al. Vasilli, P. (1992) Annu. Rev. Immunol. 10:411-452; Tracey, K. J. and Cerami, A. (1994) Annu. Rev. Med. 45:491-503).
  • hTNF ⁇ human TNF ⁇
  • therapeutic strategies have been designed to inhibit or counteract hTNF ⁇ activity.
  • antibodies that bind to, and neutralize, hTNF ⁇ have been sought as a means to inhibit hTNF ⁇ activity.
  • Some of the earliest of such antibodies were mouse monoclonal antibodies (mAbs), secreted by hybridomas prepared from lymphocytes of mice immunized with hTNF ⁇ (see e.g, Hahn T; et al., (1985) Proc Natl Acad Sci USA 82: 3814-3818; Liang, C-M., et al. (1986) Biochem. Biophys. Res. Commun.
  • mouse anti-hTNF ⁇ antibodies often displayed high affinity for hTNF ⁇ (e.g., Kd ⁇ 10 ⁇ 9 M) and were able to neutralize hTNF ⁇ activity
  • their use in vivo may be limited by problems associated with administration of mouse antibodies to humans, such as short serum half life, an inability to trigger certain human effector functions and elicitation of an unwanted immune response against the mouse antibody in a human (the “human anti-mouse antibody” (HAMA) reaction).
  • HAMA human anti-mouse antibody
  • murine anti-hTNF ⁇ antibodies have been genetically engineered to be more “human-like.”
  • chimeric antibodies in which the variable regions of the antibody chains are murine-derived and the constant regions of the antibody chains are human-derived, have been prepared (Knight, D. M, et al. (1993) Mol. Immunol. 30:1443-1453; PCT Publication No. WO 92/16553 by Daddona, P. E., et al.).
  • humanized antibodies in which the hypervariable domains of the antibody variable regions are murine-derived but the remainder of the variable regions and the antibody constant regions are human-derived, have also been prepared (PCT Publication No. WO 92/11383 by Adair, J. R., et al.).
  • HACA human anti-chimeric antibody
  • these chimeric and humanized antibodies still retain some murine sequences, they still may elicit an unwanted immune reaction, the human anti-chimeric antibody (HACA) reaction, especially when administered for prolonged periods, e.g., for chronic indications, such as rheumatoid arthritis (see e.g., Elliott, M. J., et al. (1994) Lancet 344:1125-1127; Elliot, M. J., et al. (1994) Lancet 344:1105-1110).
  • a preferred hTNF ⁇ inhibitory agent to murine mAbs or derivatives thereof would be an entirely human anti-hTNF ⁇ antibody, since such an agent should not elicit the HAMA reaction, even if used for prolonged periods.
  • Human monoclonal autoantibodies against hTNF ⁇ have been prepared using human hybridoma techniques (Boyle, P., et al. (1993) Cell. Immunol. 152:556-568; Boyle, P., et al. (1993) Cell. Immunol. 152:569-581; European Patent Application Publication No. 614 984 A2 by Boyle, et al.).
  • a stable aqueous pharmaceutical formulation with an extended shelf life comprising an antibody which is suitable for therapeutic use to inhibit or counteract detrimental hTNF ⁇ activity.
  • a stable aqueous pharmaceutical formulation with an extended shelf life comprising an antibody suitable for therapeutic use which is easily administered and contains a high protein concentration.
  • This invention provides a liquid aqueous pharmaceutical formulation consisting of a therapeutically effective amount of an antibody in a buffered solution forming a formulation having a pH between about 4 and about 8 and having a shelf life of at least 18 months.
  • the invention also includes an aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody in a buffered solution forming a formulation having a pH between about 4 and 8 and having a shelf life of at least 18 months in the liquid state.
  • the pharmaceutical formulation has enhanced stability.
  • the formulation of the invention is stable following at least 3 freeze/thaw cycles of the formulation.
  • the antibody is directed to TNF ⁇ .
  • the antibody is directed to human TNF ⁇ .
  • the antibody is D2E7.
  • This invention also provides a liquid aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody in a buffered solution forming a formulation having a pH between 4 and 8 and having enhanced stability of at least 12 months at a temperature of 2-8° C. In one embodiment, the formulation has enhanced stability of at least 18 months.
  • the antibody is directed to TNF ⁇ . In yet another embodiment, the antibody is directed to human TNF ⁇ . In a further embodiment, the antibody is D2E7.
  • the invention further provides a liquid aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody in a buffered solution forming a formulation having a pH between about 4 and about 8 which is easily administratable.
  • the antibody is directed to TNF ⁇ .
  • the antibody is directed to human TNF ⁇ .
  • the antibody is D2E7.
  • the liquid aqueous pharmaceutical formulation is suitable for injection.
  • the formulation is suitable for single use sc injection.
  • the concentration of the antibody in the liquid aqueous pharmaceutical formulation is about 1-150 mg/ml.
  • the concentration of the antibody in the formulation is about 50 mg/ml.
  • the formulation has a high protein concentration.
  • the formulation is not light sensitive.
  • the liquid aqueous pharmaceutical formulation contains an antibody, or an antigen-binding portion thereof, that dissociates from human TNF ⁇ with a K d of 1 ⁇ 10 ⁇ 8 M or less and a K off rate constant of 1 ⁇ 10 ⁇ 3 s ⁇ 1 or less, both determined by surface plasmon resonance, and neutralizes human TNF ⁇ cytotoxicity in a standard in vitro L929 assay with an IC 50 of 1 ⁇ 10 ⁇ 7 M or less.
  • the formulation of the invention contains an antibody, or antigen-binding portion thereof, which dissociates from human TNF ⁇ with a K off rate constant of 5 ⁇ 10 ⁇ 4 s ⁇ 1 or less.
  • the formulation contains an antibody, or antigen-binding portion thereof, which dissociates from human TNF ⁇ with a K off rate constant of 1 ⁇ 10 ⁇ 4 s ⁇ 1 or less.
  • the formulation of the invention contains an antibody, or antigen-binding portion thereof, which neutralizes human TNF ⁇ cytotoxicity in a standard in vitro L929 assay with an IC 50 of 1 ⁇ 10 ⁇ 8 M or less.
  • the claimed formulation includes an antibody, or antigen-binding portion thereof, which neutralizes human TNF ⁇ cytotoxicity in a standard in vitro L929 assay with an IC 50 of 1 ⁇ 10 ⁇ 9 M or less.
  • Another embodiment of the invention includes a formulation where the antibody, or antigen-binding portion thereof, neutralizes human TNF ⁇ cytotoxicity in a standard in vitro L929 assay with an IC 50 of 1 ⁇ 10 ⁇ 10 M or less.
  • the liquid aqueous pharmaceutical formulation contains of an antibody, or antigen-binding portion thereof, which is a recombinant antibody, or antigen-binding portion thereof.
  • the formulation contains an antibody, or antigen-binding portion thereof, which inhibits human TNF ⁇ -induced expression of ELAM-1 on human umbilical vein endothelial cells.
  • the claimed formulation includes the D2E7 antibody.
  • the liquid aqueous pharmaceutical formulation includes an antibody, or antigen-binding portion, thereof which dissociates from human TNF ⁇ with a K off rate constant of 1 ⁇ 10 ⁇ 3 s ⁇ 1 or less, as determined by surface plasmon resonance;
  • b) has a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9;
  • the formulation of the invention includes an antibody, or an antigen-binding portion thereof, which dissociates from human TNF ⁇ with a K off rate constant of 5 ⁇ 10 ⁇ 4 s ⁇ 1 or less.
  • the formulation includes an antibody, or an antigen-binding portion thereof, which dissociates from human TNF ⁇ with a K off rate constant of 1 ⁇ 10 ⁇ 4 s ⁇ 1 or less.
  • the liquid aqueous pharmaceutical formulation contains of an antibody, or antigen-binding portion thereof, which has a light chain variable region (LCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8, and with a heavy chain variable region (HCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11.
  • LCVR light chain variable region
  • HCVR heavy chain variable region
  • the formulation of the invention contains an antibody, wherein the LCVR of the antibody, or an antigen-binding portion thereof, further has a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5 and the HCVR of the antibody, or an antigen-binding portion thereof, further has a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 6.
  • the formulation of the invention contains an antibody, wherein the LCVR of the antibody, or an antigen-binding portion thereof, further has CDR1 domain comprising the amino acid sequence of SEQ ID NO: 7 and the HCVR has a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 8.
  • the antibody or antigen-binding portion thereof, contained in the liquid aqueous pharmaceutical formulation has a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2.
  • LCVR light chain variable region
  • HCVR heavy chain variable region
  • the antibody, or antigen-binding portion thereof has an IgG1 heavy chain constant region.
  • the antibody, or antigen-binding portion thereof has an IgG4 heavy chain constant region.
  • the antibody, or antigen-binding portion thereof is a Fab fragment.
  • the antibody, or antigen-binding portion thereof is a single chain Fv fragment.
  • the liquid aqueous pharmaceutical formulation contains an antibody, or antigen-binding portion thereof, which has a light chain variable region (LCVR) having a CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 or with a heavy chain variable region (HCVR) having a CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 34
  • LCVR light chain variable region
  • the antibody, or antigen-binding portion thereof neutralizes the activity of human TNF ⁇ , chimpanzee TNF ⁇ and at least one additional primate TNF ⁇ selected from the group consisting of baboon TNF ⁇ , marmoset TNF ⁇ , cynomolgus TNF ⁇ and rhesus TNF ⁇ .
  • the formulation of the invention includes an antibody, or an antigen-binding portion thereof, which also neutralizes the activity of mouse TNF ⁇ .
  • the formulation of the invention also an antibody, or an antigen-binding portion thereof, which neutralizes the activity of pig TNF ⁇ .
  • the invention provides a liquid aqueous pharmaceutical formulation which contains an antibody, or antigen-binding portion thereof, which binds to human TNF ⁇ and comprises:
  • a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9, and
  • a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12.
  • the liquid aqueous pharmaceutical formulation includes an antibody which bind human TNF ⁇ and comprises a light chain variable region (LCVR) having a CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 or a heavy chain variable region (HCVR) having a CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 34.
  • the antibody which bind human TNF ⁇ and comprises
  • the invention also provides an aqueous pharmaceutical composition
  • a polyol comprising a polyol, a surfactant, and a buffer system comprising citrate and/or phosphate with a pH of about 4 to 8, in amounts sufficient to formulate an antibody for therapeutic use at a concentration of greater than about 45 mg/ml.
  • the polyol is mannitol and the surfactant is polysorbate 80.
  • the composition includes 5-20 mg/ml of mannitol and 0.1-10 mg/ml of polysorbate 80.
  • the composition includes the antibody D2E7.
  • the invention also provides a liquid aqueous pharmaceutical formulation consisting of 1-150 mg/ml of antibody, 5-20 mg/ml of mannitol, 0.1-10 mg/ml of Tween-80, and a buffer system comprising citrate and/or phosphate, with a pH of 4 to 8.
  • the antibody is directed to hTNF ⁇ .
  • the formulation contains about 40 mg of antibody.
  • the invention further provides a liquid aqueous pharmaceutical formulation comprising about 50 mg/ml of antibody, about 12 mg/ml of mannitol, about 1 mg/ml of Tween-80, and a buffer system comprising citrate and/or phosphate, with a pH of about 4 to about 8.
  • the pH of the formulation is between about 4.5 to about 6.0.
  • the pH is between about 4.8 to about 5.5.
  • the pH of the invention is between about 5.0 to about 5.2.
  • the liquid aqueous pharmaceutical formulation also includes about 1.305 mg/ml of citric acid, about 0.305 mg/ml of sodium citrate, about 1.53 mg/ml of disodium phosphate dihydrate, about 0.86 mg/ml of sodium dihydrogen phosphate dihydrate, and about 6.165 mg/ml of sodium chloride.
  • the formulation of the invention includes an antibody which is directed to hTNF ⁇ .
  • the formulation of the invention includes the antibody D2E7.
  • the formulation of the invention is administered to a subject suffering from a disorder in which TNF ⁇ activity is detrimental such that TNF ⁇ activity in the subject is inhibited
  • This invention pertains to a liquid aqueous pharmaceutical formulation with a pH of about 4 to about 8 which contains a high protein concentration, including an antibody concentration ranging from about 1 to about 150 mg/ml, and has enhanced stability.
  • This invention also pertains to a liquid aqueous pharmaceutical formulation for therapeutic use in a subject suffering from a condition characterized by detrimental TNF ⁇ activity.
  • the formulation of the invention comprises the following constituents: an antibody which binds to human TNF ⁇ with high affinity, a low off rate and high neutralizing capacity; a buffer, which includes citric acid, sodium citrate, disodium phosphate dihydrate, and sodium dihydrogen phosphate dihydrate; tonicity agents, which include mannitol and sodium chloride; a detergent, including polysorbate 80; and sodium hydroxide, for pH adjustment.
  • subject is intended to include living organisms, e.g., prokaryotes and eukaryotes.
  • subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals.
  • the subject is a human.
  • pharmaceutical formulation refers to preparations which are in such form as to permit the biological activity of the active ingredients to be unequivocally effective, and which contain no additional components which are significantly toxic to the subjects to which the formulation would be administered.
  • “Pharmaceutically acceptable” excipients are those which can reasonably be administered to a subject mammal to provide an effective dose of the active ingredient employed.
  • a “stable” formulation is one in which the antibody therein essentially retains its physical stability and/or chemical stability and/or biological activity upon storage.
  • Various analytical techniques for measuring protein stability are available in the art and are reviewed in Peptide and Protein Drug Delivery, 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York, N.Y., Pubs. (1991) and Jones, A. Adv. Drug Delivery Rev. 10: 35 29-90 (1993), for example.
  • Stability can be measured at a selected temperature for a selected time period.
  • the formulation is stable at room temperature (about 30° C.) or at 40° C. for at least 1 month and/or stable at about 2-8° C. for at least 1 year for at least 2 years.
  • the formulation is preferably stable following freezing (to, e.g., ⁇ 70° C.) and thawing of the formulation, hereinafter referred to as a “freeze/thaw cycle.”
  • An antibody “retains its physical stability” in a pharmaceutical formulation if it shows substantially no signs of aggregation, precipitation and/or denaturation upon visual examination of color and/or clarity, or as measured by UV light scattering or by size exclusion chromatography.
  • An antibody “retains its chemical stability” in a pharmaceutical formulation if the chemical stability at a given time is such that the antibody is considered to still retain its biological activity as defined below.
  • Chemical stability can be assessed by detecting and quantifying chemically altered forms of the antibody.
  • Chemical alteration may involve size modification (e.g. clipping) which can be evaluated using size exclusion chromatography, SDS-PAGE and/or matrix-assisted laser desorption ionization/time-of-flight mass spectrometry (MALDI/TOF MS), for example.
  • Other types of chemical alteration include charge alteration (e.g. occurring as a result of deamidation) which can be evaluated by ion-exchange chromatography, for example.
  • An antibody “retains its biological activity” in a pharmaceutical formulation, if the antibody in a pharmaceutical formulation is biologically active for its intended purpose. For example, biological activity is retained if the biological activity of the antibody in the pharmaceutical formulation is within about 30%, about 20%, or about 10% (within the errors of the assay) of the biological activity exhibited at the time the pharmaceutical formulation was prepared (e.g., as determined in an antigen binding assay).
  • Isotonic is a term recognized in the art. Isotonic can mean, for example, that the formulation of interest has essentially the same osmotic pressure as human blood. Isotonic formulations will generally have an osmotic pressure from about 250 to 350 mOsm. Isotonicity can be measured using a vapor pressure or ice-freezing type osmometer, for example. A “tonicity agent” is a compound which renders the formulation isotonic.
  • a “polyol” is a substance with multiple hydroxyl groups, and includes sugars (reducing and nonreducing sugars), sugar alcohols and sugar acids. Preferred polyols herein have a molecular weight which is less than about 600 kD (e.g. in the range from about 120 to about 400 kD).
  • a “reducing sugar” is one which contains a hemiacetal group that can reduce metal ions or react covalently with lysine and other amino groups in proteins and a “nonreducing sugar” is one which does not have these properties of a reducing sugar.
  • reducing sugars are fructose, mannose, maltose, lactose, arabinose, xylose, ribose, rhamnose, galactose and glucose.
  • Nonreducing sugars include sucrose, trehalose, sorbose, melezitose and raffinose.
  • Mannitol, xylitol, erythritol, threitol, sorbitol and glycerol are examples of sugar alcohols.
  • sugar acids these include L-gluconate and metallic salts thereof.
  • the polyol is preferably one which does not crystallize at freezing temperatures (e.g.
  • one ingredient of the formulation is mannitol in a concentration of 5 to 20 mg/ml. In a preferred embodiment of the invention, the concentration of mannitol is 7.5 to 15 mg/ml. In a more preferred embodiment of the invention, the concentration of mannitol is 10-14 mg/ml.
  • buffer refers to a buffered solution that resists changes in pH by the action of its acid-base conjugate components.
  • the buffer of this invention has a pH in the range from about 4 to about 8; preferably from about 4.5 to about 7; and most preferably has a pH in the range from about 5.0 to about 6.5.
  • buffers that will control the pH in this range include acetate (e.g. sodium acetate), succinate (such as sodium succinate), gluconate, histidine, citrate and other organic acid buffers.
  • a “therapeutically effective amount” or “effective amount” of an antibody refers to an amount effective in the prevention or treatment of a disorder for the treatment of which the antibody is effective.
  • a “disorder” is any condition that would benefit from treatment with the antibody. This includes chronic and acute disorders or diseases including those pathological conditions which predisposes the subject to the disorder in question.
  • a “preservative” is a compound which can be included in the formulation to essentially reduce bacterial action therein, thus facilitating the production of a multi-use formulation, for example.
  • potential preservatives include octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride (a mixture of alkylbenzyldimethylammonium chlorides in which the alkyl groups are long-chain compounds), and benzethonium chloride.
  • preservatives include aromatic alcohols such as phenol, butyl and benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol.
  • Treatment refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disorder as well as those in which the disorder is to be prevented.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • phrases “pharmaceutically acceptable carrier” is art recognized and includes a pharmaceutically acceptable material, composition or vehicle, suitable for administration to mammals.
  • the carriers include liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • hTNF ⁇ human TNF ⁇
  • hTNF ⁇ human cytokine that exists as a 17 kD secreted form and a 26 kD membrane associated form, the biologically active form of which is composed of a trimer of noncovalently bound 17 kD molecules.
  • the structure of hTNF ⁇ is described further in, for example, Pennica, D., et al. (1984) Nature 312:724-729; Davis, J. M., et al. (1987) Biochemistry 26:1322-1326; and Jones, E. Y., et al. (1989) Nature 338:225-228.
  • human TNF ⁇ is intended to include recombinant human TNF ⁇ (rhTNF ⁇ ), which can be prepared by standard recombinant expression methods or purchased commercially (R & D Systems, Catalog No. 210-TA, Minneapolis, Minn.).
  • antibody is intended to refer to immunoglobulin molecules comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds.
  • Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region.
  • the heavy chain constant region is comprised of three domains, CH1, CH2 and CH3.
  • Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region.
  • the light chain constant region is comprised of one domain, CL.
  • VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the formulation contains an antibody with CDR1, CDR2, and CDR3 sequences like those described in U.S. Pat. Nos. 6,090,382 and 6,258,562, each incorporated by reference herein.
  • antigen-binding portion of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., hTNF ⁇ ). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.
  • binding fragments encompassed within the term “antigen-binding portion” of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) a F(ab′) 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., (1989) Nature 341:544-546 ), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR).
  • a Fab fragment a monovalent fragment consisting of the VL, VH, CL and CHI domains
  • a F(ab′) 2 fragment a bivalent fragment comprising two Fab fragments linked by
  • the two domains of the Fv fragment, VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883).
  • single chain Fv single chain Fv
  • Such single chain antibodies are also intended to be encompassed within the term “antigen-binding portion” of an antibody.
  • Other forms of single chain antibodies, such as diabodies are also encompassed.
  • Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites (see e.g., Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, R. J., et al. (1994) Structure 2:1121-1123).
  • the formulation contains an antigen-binding portions described in U.S. Pat. Nos. 6,090,382 and 6,258,562, each incorporated by reference herein.
  • an antibody or antigen-binding portion thereof may be part of a larger immunoadhesion molecules, formed by covalent or noncovalent association of the antibody or antibody portion with one or more other proteins or peptides.
  • immunoadhesion molecules include use of the streptavidin core region to make a tetrameric scFv molecule (Kipriyanov, S. M., et al. (1995) Human Antibodies and Hybridomas 6:93- 101) and use of a cysteine residue, a marker peptide and a C-terminal polyhistidine tag to make bivalent and biotinylated scFv molecules (Kipriyanov, S. M., et al.
  • Antibody portions such as Fab and F(ab′) 2 fragments, can be prepared from whole antibodies using conventional techniques, such as papain or pepsin digestion, respectively, of whole antibodies.
  • antibodies, antibody portions and immunoadhesion molecules can be obtained using standard recombinant DNA techniques, as described herein.
  • human antibody is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences.
  • the human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3.
  • the term “human antibody”, as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • recombinant human antibody is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further in Section II, below), antibodies isolated from a recombinant, combinatorial human antibody library (described further in Section III, below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor, L. D., et al. (1992) Nucl. Acids Res.
  • Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
  • an “isolated antibody”, as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds hTNF ⁇ is substantially free of antibodies that specifically bind antigens other than hTNF ⁇ .
  • An isolated antibody that specifically binds hTNF ⁇ may, however, have cross-reactivity to other antigens, such as TNF ⁇ molecules from other species.
  • an isolated antibody may be substantially free of other cellular material and/or chemicals.
  • a “neutralizing antibody”, as used herein is intended to refer to an antibody whose binding to hTNF ⁇ results in inhibition of the biological activity of hTNF ⁇ .
  • This inhibition of the biological activity of hTNF ⁇ can be assessed by measuring one or more indicators of hTNF ⁇ biological activity, such as hTNF ⁇ -induced cytotoxicity (either in vitro or in vivo), hTNF ⁇ -induced cellular activation and hTNF ⁇ binding to hTNF ⁇ receptors.
  • indicators of hTNF ⁇ biological activity can be assessed by one or more of several standard in vitro or in vivo assays known in the art, and described in U.S. Pat. Nos.
  • the ability of an antibody to neutralize hTNF ⁇ activity is assessed by inhibition of hTNF ⁇ -induced cytotoxicity of L929 cells.
  • the ability of an antibody to inhibit hTNF ⁇ -induced expression of ELAM-1 on HUVEC, as a measure of hTNF ⁇ -induced cellular activation can be assessed.
  • surface plasmon resonance refers to an optical phenomenon that allows for the analysis of real-time biospecific interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIAcore system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.).
  • BIAcore Pharmaacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.
  • K off is intended to refer to the off rate constant for dissociation of an antibody from the antibody/antigen complex.
  • K d is intended to refer to the dissociation constant of a particular antibody-antigen interaction.
  • the invention is directed to a liquid aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody in a buffered solution forming a formulation having a pH between about 4 and about 8 and having an extended shelf life, preferably of at least about 18 months.
  • the liquid aqueous pharmaceutical formulation of the invention has enhanced stability.
  • the formulation is not light sensitive.
  • the claimed formulation remains stable following at least 3 freeze/thaw cycles.
  • the pharmaceutical formulation of the invention is suitable for single use sc injection.
  • Antibodies that can be used in the formulation include polyclonal, monoclonal, recombinant antibodies, single chain antibodies, hybrid antibodies, chimeric antibodies, humanized antibodies, or fragments thereof.
  • Antibody-like molecules containing one or two binding sites for an antigen and a Fc-part of an immunoglobulin can also be used.
  • An example of an antibody-like molecule is the active ingredient etanercept or infliximab.
  • Preferred antibodies used in the formulation are human antibodies which are cloned from human cells or from gene-archives representing the human antibody-reservoir.
  • Especially preferred among the human antibodies are antibodies directed against the antigen TNF ⁇ , including human TNF ⁇ (or hTNF ⁇ ).
  • the formulation of the invention includes a combination of antibodies (two or more), or a “cocktail” of antibodies.
  • the formulation can include the antibody D2E7 and one or more additional antibodies.
  • the formulation contains an antibody, or antigen-binding portion thereof, dissociates from human TNF ⁇ with a K d of 1 ⁇ 10 ⁇ 8 M or less and a K off rate constant of 1 ⁇ 10 ⁇ 3 s ⁇ 1 or less, both determined by surface plasmon resonance, and neutralizes human TNF ⁇ cytotoxicity in a standard in vitro L929 assay with an IC 50 of 1 ⁇ 10 ⁇ 7 M or less.
  • the formulation of the invention contains an antibody, or antigen-binding portion thereof, like those described in U.S. Pat. Nos. 6,090,382 and 6,258,562, each incorporated by reference herein.
  • the formulation of the invention contains D2E7 antibodies and antibody portions, D2E7-related antibodies and antibody portions, and other human antibodies and antibody portions with equivalent properties to D2E7, such as high affinity binding to hTNF ⁇ with low dissociation kinetics and high neutralizing capacity.
  • the formulation of the invention contains an isolated human antibody, or an antigen-binding portion thereof, that dissociates from human TNF ⁇ with a K d of 1 ⁇ 10 ⁇ 8 M or less and a K off rate constant of 1 ⁇ 10 ⁇ 3 s ⁇ 1 or less, both determined by surface plasmon resonance, and neutralizes human TNF ⁇ cytotoxicity in a standard in vitro L929 assay with an IC 50 of 1 ⁇ 10 ⁇ 7 M or less.
  • the isolated human antibody, or antigen-binding portion thereof dissociates from human TNF ⁇ with a K off of 5 ⁇ 10 ⁇ 4 s ⁇ 1 or less, or even more preferably, with a K off of 1 ⁇ 10 ⁇ 4 s ⁇ 1 or less. More preferably, the isolated human antibody, or antigen-binding portion thereof, neutralizes human TNF ⁇ cytotoxicity in a standard in vitro L929 assay with an IC 50 of 1 ⁇ 10 ⁇ 8 M or less, even more preferably with an IC 50 of 1 ⁇ 10 ⁇ 9 M or less and still more preferably with an IC 50 of 5 ⁇ 10 ⁇ 10 M or less.
  • the formulation contains an antibody which is an isolated human recombinant antibody, or an antigen-binding portion thereof.
  • the formulation contains an antibody which also neutralizes TNF ⁇ -induced cellular activation, as assessed using a standard in vitro assay for TNF ⁇ -induced ELAM-1 expression on human umbilical vein endothelial cells (HUVEC).
  • the present invention features formulations (e.g., protein formulations and/or antibody formulations) having improved properties as compared to art-recognized formulations.
  • the formulations of the invention have an improved shelf life and/or stability as compared to art recognized formulations.
  • the formulations of the invention comprise a high protein concentration, including, for example, a protein concentration greater than about 45 mg/ml, a protein concentration greater than about 50 mg/ml, a protein concentration greater than about 100 mg/ml, or a protein concentration greater than about 150 mg/ml.
  • the protein is an antibody.
  • the antibody is D2E7.
  • the invention also provides an aqueous pharmaceutical composition
  • a aqueous pharmaceutical composition comprising a polyol, a surfactant, and a buffer system comprising citrate and/or phosphate with a pH of about 4 to 8, in amounts sufficient to formulate an antibody for therapeutic use at a concentration of greater than about, for example, 45 mg/ml.
  • the antibody of interest is performed according to standard methods known in the art.
  • the antibody used in the formulation is expressed in CHO cells and purified by a standard series of chromatography steps.
  • the antibody is directed to hTNF ⁇ , and is prepared according to the methods described in U.S. Pat. Nos. 6,090,382 and 6,258,562, each incorporated by reference herein.
  • the pharmaceutical formulation comprising the antibody is prepared.
  • the therapeutically effective amount of antibody present in the formulation is determined, for example, by taking into account the desired dose volumes and mode(s) of administration.
  • the concentration of the antibody in the formulation is between about 1 to about 150 mg of antibody per ml of liquid formulation. In a preferred embodiment, the concentration of the antibody in the formulation is between about 5 to about 80 mg per ml. In another preferred embodiment, the concentration of the antibody in the formulation is between about 25 to about 50 mg/ml.
  • the formulation is especially suitable for large antibody dosages of more than 15 mg/ml. In a preferred embodiment, the concentration of the antibody is 50 mg/ml.
  • the concentration of the antibody in the formulation is about 1-150 mg/ml, about 5-145 mg/ml, about 10-140 mg/ml, about 15-135 mg/ml, about 20-130 mg/ml, about 25-125 mg/ml, about 30-120 mg/ml, about 35-115 mg/ml, about 40-110 mg/ml, about 45-105 mg/ml, about 50-100 mg/ml, about 55-95 mg/ml, about 60-90 mg/ml, about 65-85 mg/ml, about 70-80 mg/ml, or about 75 mg/ml.
  • Ranges intermediate to the above recited concentrations are also intended to be part of this invention.
  • ranges of values using a combination of any of the above recited values as upper and/or lower limits are intended to be included.
  • the invention provides a formulation with an extended shelf life comprising of an active ingredient, preferably an antibody, in combination with mannitol, citric acid monohydrate, sodium citrate, disodium phosphate dihydrate, sodium dihydrogen phosphate dihydrate, sodium chloride, polysorbate 80, water, and sodium hydroxide.
  • the formulation of the invention has an extended shelf life of at least about 18 months in the liquid state. Freezing the formulation of the invention can also be used to further extend its shelf life.
  • An aqueous formulation is prepared comprising the antibody in a pH-buffered solution.
  • the buffer of this invention has a pH ranging from about 4 to about 8, preferably from about 4.5 to about 6.0, more preferably from about 4.8 to about 5.5, and most preferably has a pH of about 5.0 to about 5.2. Ranges intermediate to the above recited pH's are also intended to be part of this invention. For example, ranges of values using a combination of any of the above recited values as upper and/or lower limits are intended to be included. Examples of buffers that will control the pH within this range include acetate (e.g. sodium acetate), succinate (such as sodium succinate), gluconate, histidine, citrate and other organic acid buffers.
  • the formulation comprises a buffer system which contains citrate and phosphate to maintain the pH in a range of about 4 to about 8.
  • the pH range is from about 4.5 to about 6.0, more preferably from about pH 4.8 to about 5.5, and most preferably in a pH range of about 5.0 to about 5.2.
  • the buffer system includes citric acid monohydrate, sodium citrate, disodium phosphate dihydrate, and/or sodium dihydrogen phosphate dihydrate.
  • the buffer system includes about 1.3 mg/ml of citric acid (e.g., 1.305 mg/ml), about 0.3 mg/ml of sodium citrate (e.g., 0.305 mg/ml), about 1.5 mg/ml of disodium phosphate dihydrate (e.g. 1.53 mg/ml), about 0.9 mg/ml of sodium dihydrogen phosphate dihydrate (e.g., 0.86), and about 6.2 mg/ml of sodium chloride (e.g., 6.165 mg/ml).
  • citric acid e.g., 1.305 mg/ml
  • sodium citrate e.g. 0.305 mg/ml
  • 1.5 mg/ml of disodium phosphate dihydrate e.g. 1.53 mg/ml
  • about 0.9 mg/ml of sodium dihydrogen phosphate dihydrate e.g. 0.86
  • about 6.2 mg/ml of sodium chloride e.g., 6.165 mg/ml
  • the buffer system includes 1-1.5 mg/ml of citric acid, 0.25 to 0.5 mg/ml of sodium citrate, 1.25 to 1.75 mg/ml of of disodium phosphate dihydrate, 0.7 to 1.1 mg/ml of sodium dihydrogen phosphate dihydrate, and 6.0 to 6.4 mg/ml of sodium chloride.
  • the pH of the formulation is adjusted with sodium hydroxide.
  • a polyol which acts as a tonicifier and may stabilize the antibody, is also included in the formulation.
  • the polyol is added to the formulation in an amount which may vary with respect to the desired isotonicity of the formulation.
  • the aqueous formulation is isotonic.
  • the amount of polyol added may also alter with respect to the molecular weight of the polyol. For example, a lower amount of a monosaccharide (e.g. mannitol) may be added, compared to a disaccharide (such as trehalose).
  • the polyol which is used in the formulation as a tonicity agent is mannitol.
  • the mannitol concentration is about 5 to 20 mg/ml. In another preferred embodiment of the invention, the concentration of mannitol is about 7.5 to 15 mg/ml. In a more preferred embodiment of the formulation of the invention, the concentration of mannitol is about 10-14 mg/ml. In the most preferred embodiment, the concentration of mannitol is about 12 mg/ml. In another embodiment of the invention, the polyol sorbitol is included in the formulation.
  • a detergent or surfactant is also added to the antibody formulation.
  • exemplary detergents include nonionic detergents such as polysorbates (e.g. polysorbates 20, 80 etc) or poloxamers (e.g. poloxamer 188).
  • the amount of detergent added is such that it reduces aggregation of the formulated antibody and/or minimizes the formation of particulates in the formulation and/or reduces adsorption.
  • the formulation includes a surfactant which is a polysorbate.
  • the formulation contains the detergent polysorbate 80 or Tween 80.
  • Tween 80 is a term used to describe polyoxyethylene (20) sorbitanmonooleate (see Fiedler, Lexikon der Hifsstoffe, Editio Cantor Verlag Aulendorf, 4th edi., 1996).
  • the formulation contains between about 0.1 and about 10 mg/ml of polysorbate 80, more preferably between about 0.5 and about 5 mg/ml. In another preferred embodiment, about 0.1% polysorbate 80 is found in the formulation of the invention.
  • the formulation is a 0.8 mL solution in a vial containing the ingredients shown below in Table 1.
  • TABLE 1 1 vial with 0.8 mL solution for injection 1) contains: Name of ingredient Quantity Function Active substance: Antibody (D2E7) 2) 40.0 mg Active substance Excipients: Mannitol 9.6 mg Tonicity agent Citric acid monohydrate 1.044 mg Buffer Citric acid Sodium citrate 0.244 mg Buffer Sodium citrate Disodium phosphate 1.224 mg Buffer dihydrate Dibasic sodium phosphate dihydrate Sodium dihydrogen 0.688 mg Buffer phosphate dihydrate Monobasic sodium phosphate dihydrate Sodium chloride 4.932 mg Tonicity agent Polysorbate 80 0.8 mg Detergent Water for injections 759.028-759.048 mg Solvent Water for injection Sodium hydroxide 3) 0.02-0.04 mg pH adjustment Total 817.6 mg
  • the formulation contains the above-identified agents (i.e. antibody, buffer, polyol and detergent) and is essentially free of one or more preservatives, such as benzyl alcohol, phenol, m-cresol, chlorobutanol and benzethonium Cl.
  • a preservative may be included in the formulation, particularly where the formulation is a multidose formulation.
  • One or more other pharmaceutically acceptable carriers, excipients or stabilizers such as those described in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980) may be included in the formulation provided that they do not significantly adversely affect the desired characteristics of the formulation.
  • Acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed and include; additional buffering agents; co-solvents; antioxidants including ascorbic acid and methionine; chelating agents such as EDTA; metal complexes (e.g. Zn-protein complexes); biodegradable polymers such as polyesters; and/or salt-forming counterions such as sodium.
  • the formulation herein may also be combined with one or more other therapeutic agents as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect the antibody of the formulation.
  • Such therapeutic agents are suitably present in combination in amounts that are effective for the purpose intended. Additional therapeutic agents which can be combined with the formulation of the invention are further described in U.S. Pat. Nos. 6,090,382 and 6,258,562, each of which is incorporated herein by reference.
  • the formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes, prior to, or following, preparation of the formulation.
  • the language “effective amount” of the formulation is that amount necessary or sufficient to inhibit TNF ⁇ activity, e.g., prevent the various morphological and somatic symptoms of a detrimental TNF ⁇ activity-associated state.
  • the effective amount of the formulation is the amount necessary to achieve the desired result.
  • an effective amount of the formulation is the amount sufficient to inhibit detrimental TNF ⁇ activity.
  • an effective amount of the formulation is 0.8 mL of the formulation containing 40 mg of antibody, as described in table 1.
  • the effective amount can vary depending on such factors as the size and weight of the subject, or the type of illness. For example, the choice of a TNF ⁇ activity-inhibiting formulation can affect what constitutes an “effective amount”.
  • One of ordinary skill in the art would be able to study the aforementioned factors and make the determination regarding the effective amount of the TNF ⁇ activity inhibiting formulation without undue experimentation.
  • the regimen of administration can affect what constitutes an effective amount.
  • the TNF ⁇ activity-inhibiting formulation can be administered to the subject either prior to or after the onset of detrimental TNF ⁇ activity. Further, several divided dosages, as well as staggered dosages, can be administered daily or sequentially, or the dose can be continuously infused, or can be a bolus injection. Further, the dosages of the TNF ⁇ activity-inhibiting formulation can be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.
  • treatment includes the diminishment or alleviation of at least one symptom associated or caused by the state, disorder or disease being treated.
  • treatment can be diminishment of one or several symptoms of a disorder or complete eradication of a disorder.
  • Actual dosage levels of the active ingredients (antibody) in the pharmaceutical formulation of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the antibody found in the formulation, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition of the present invention required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical formulation at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a formulation of the invention will be that amount of the formulation that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • An effective amount of the formulation of the present invention is an amount that inhibits TNF ⁇ activity in a subject suffering from a disorder in which TNF ⁇ activity is detrimental.
  • the formulation provides an effective dose of 40 mg per injection of the active ingredient, the antibody.
  • the formulation provides an effective dose which ranges from about 1 to 150 mg of antibody.
  • the effective daily dose of the pharmaceutical formulation may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the dosage of the antibody in the formulation is between about 5 to about 80 mg. In another embodiment, the dosage of the antibody in the formulation is between about 25 to about 50 mg.
  • the formulation is especially suitable for large antibody dosages of more than 15 mg.
  • the formulation provides an antibody at a dose of about 40 mg.
  • the antibody is directed to TNF ⁇ . In the most preferred embodiment, the antibody is D2E7.
  • the dosage of the antibody in the formulation is between about 1-150 mg, about 5-145 mg, about 10-140 mg, about 15-135 mg, about 20-130 mg, about 25-125 mg, about 30-120 mg, about 35-115 mg, about 40-110 mg, about 45-105 mg, about 50-100 mg, about 55-95 mg, about 60-90 mg, about 65-85 mg, about 70-80 mg, or about 75 mg.
  • the dosage of the antibody is 40 mg.
  • the antibody is directed to TNF ⁇ .
  • the antibody is D2E7. Ranges intermediate to the above recited dosages, e.g., about 2-149 mg, are also intended to be part of this invention. For example, ranges of values using a combination of any of the above recited values as upper and/or lower limits are intended to be included.
  • dosage values may vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • the invention provides a pharmaceutical formulation with an extended shelf life, which, in one embodiment, is used to inhibit TNF ⁇ activity in a subject suffering from a disorder in which TNF ⁇ activity is detrimental, comprising administering to the subject an antibody or antibody portion of the invention such that TNF ⁇ activity in the subject is inhibited.
  • the TNF ⁇ is human TNF ⁇ and the subject is a human subject.
  • the subject can be a mammal expressing a TNF ⁇ with which an antibody of the invention cross-reacts.
  • the subject can be a mammal into which has been introduced hTNF ⁇ (e.g., by administration of hTNF ⁇ or by expression of an hTNF ⁇ transgene).
  • a formulation of the invention can be administered to a human subject for therapeutic purposes (discussed further below).
  • the liquid pharmaceutical formulation is easily administratable, which includes, for example, a formulation which is self-administered by the patient.
  • the formulation of the invention is administered through sc injection, preferably single use.
  • a formulation of the invention can be administered to a non-human mammal expressing a TNF ⁇ with which the antibody cross-reacts (e.g., a primate, pig or mouse) for veterinary purposes or as an animal model of human disease. Regarding the latter, such animal models may be useful for evaluating the therapeutic efficacy of antibodies of the invention (e.g., testing of dosages and time courses of administration).
  • a disorder in which TNF ⁇ activity is detrimental is intended to include diseases and other disorders in which the presence of TNF ⁇ in a subject suffering from the disorder has been shown to be or is suspected of being either responsible for the pathophysiology of the disorder or a factor that contributes to a worsening of the disorder. Accordingly, a disorder in which TNF ⁇ activity is detrimental is a disorder in which inhibition of TNF ⁇ activity is expected to alleviate the symptoms and/or progression of the disorder. Such disorders may be evidenced, for example, by an increase in the concentration of TNF ⁇ in a biological fluid of a subject suffering from the disorder (e.g., an increase in the concentration of TNF ⁇ in serum, plasma, synovial fluid, etc. of the subject), which can be detected, for example, using an anti-TNF ⁇ antibody as described above.
  • TNF ⁇ activity is detrimental.
  • disorders in which TNF ⁇ activity is detrimental are described in U.S. application Ser. No. 60/397275, incorporated by reference herein.
  • Examples in which TNF ⁇ activity is detrimental are also described in U.S. Pat. Nos. 6,015,557, 6,177,077, 6,379,666, 6,419,934, 6,419,944, 6,423,321, and 6,428,787; U.S. patent application Ser. Nos. US2001/0016195, US2001/0004456, and US2001/026801; WO 00/50079 and WO 01/49321, each incorporated by reference herein.
  • Tumor necrosis factor has an established role in the pathophysiology of sepsis, with biological effects that include hypotension, myocardial suppression, vascular leakage syndrome, organ necrosis, stimulation of the release of toxic secondary mediators and activation of the clotting cascade (see e.g., Tracey, K. J. and Cerami, A. (1994) Annu. Rev. Med. 45:491-503; Russell, D and Thompson, R. C. (1993) Curr. Opin. Biotech. 4:714-721). Accordingly, the formulation of the invention can be used to treat sepsis in any of its clinical settings, including septic shock, endotoxic shock, gram negative sepsis and toxic shock syndrome.
  • the formulation of the invention can be coadministered with one or more additional therapeutic agents that may further alleviate sepsis, such as an interleukin-1 inhibitor (such as those described in PCT Publication Nos. WO 92/16221 and WO 92/17583), the cytokine interleukin-6 (see e.g., PCT Publication No. WO 93/11793) or an antagonist of platelet activating factor (see e.g., European Patent Application Publication No. EP 374 510).
  • an interleukin-1 inhibitor such as those described in PCT Publication Nos. WO 92/16221 and WO 92/17583
  • the cytokine interleukin-6 see e.g., PCT Publication No. WO 93/11793
  • an antagonist of platelet activating factor see e.g., European Patent Application Publication No. EP 374 510.
  • the formulation of the invention is administered to a human subject within a subgroup of sepsis patients having a serum or plasma concentration of IL-6 above 500 pg/ml, and more preferably 1000 pg/ml, at the time of treatment (see PCT Publication No. WO 95/20978 by Daum, L., et al.).
  • Tumor necrosis factor has been implicated in playing a role in the pathophysiology of a variety of autoimmune diseases.
  • TNF ⁇ has been implicated in activating tissue inflammation and causing joint destruction in rheumatoid arthritis (see e.g., Tracey and Cerami, supra; Arend, W. P. and Dayer, J-M. (1995) Arth. Rheum. 38:151-160; Fava, R. A., et al. (1993) Clin. Exp. Immunol. 94:261-266).
  • TNF ⁇ also has been implicated in promoting the death of islet cells and in mediating insulin resistance in diabetes (see e.g., Tracey and Cerami, supra; PCT Publication No.
  • TNF ⁇ also has been implicated in mediating cytotoxicity to oligodendrocytes and induction of inflammatory plaques in multiple sclerosis (see e.g., Tracey and Cerami, supra).
  • Chimeric and humanized murine anti-hTNF ⁇ antibodies have undergone clinical testing for treatment of rheumatoid arthritis (see e.g., Elliott, M. J., et al. (1994) Lancet 344:1125-1127; Elliot, M. J., et al. (1994) Lancet 344:1105-1110; Rankin, E. C., et al. (1995) Br. J. Rheumatol. 34:334-342).
  • the formulation of the invention can be used to treat autoimmune diseases, in particular those associated with inflammation, including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and gouty arthritis, allergy, multiple sclerosis, autoimmune diabetes, autoimmune uveitis and nephrotic syndrome.
  • the formulation is administered systemically, although for certain disorders, local administration of the antibody or antibody portion at a site of inflammation may be beneficial (e.g., local administration in the joints in rheumatoid arthritis or topical application to diabetic ulcers, alone or in combination with a cyclohexane-ylidene derivative as described in PCT Publication No. WO 93/19751).
  • Tumor necrosis factor has been implicated in mediating biological effects observed in a variety of infectious diseases.
  • TNF ⁇ has been implicated in mediating brain inflammation and capillary thrombosis and infarction in malaria (see e.g., Tracey and Cerami, supra).
  • TNF ⁇ also has been implicated in mediating brain inflammation, inducing breakdown of the blood-brain barrier, triggering septic shock syndrome and activating venous infarction in meningitis (see e.g., Tracey and Cerami, supra).
  • TNF ⁇ also has been implicated in inducing cachexia, stimulating viral proliferation and mediating central nervous system injury in acquired immune deficiency syndrome (AIDS) (see e.g., Tracey and Cerami, supra).
  • AIDS acquired immune deficiency syndrome
  • the antibodies, and antibody portions, of the invention can be used in the treatment of infectious diseases, including bacterial meningitis (see e.g., European Patent Application Publication No. EP 585 705), cerebral malaria, AIDS and AIDS-related complex (ARC) (see e.g., European Patent Application Publication No. EP 230 574), as well as cytomegalovirus infection secondary to transplantation (see e.g., Fietze, E., et al. (1994) Transplantation 58:675-680).
  • infectious diseases including bacterial meningitis (see e.g., European Patent Application Publication No. EP 585 705), cerebral malaria, AIDS and AIDS-related complex (ARC) (see e.g., European Patent Application Publication No. EP 230 574), as well as cytomegalovirus infection secondary to transplantation (see e.g., Fietze, E., et al. (1994) Transplantation 58:675-680).
  • the formulation of the invention also
  • Tumor necrosis factor has been implicated as a key mediator of allograft rejection and graft versus host disease (GVHD) and in mediating an adverse reaction that has been observed when the rat antibody OKT3, directed against the T cell receptor CD3 complex, is used to inhibit rejection of renal transplants (see e.g., Tracey and Cerami, supra; Eason, J. D., et al. (1995) Transplantation 59:300-305; Suthanthiran, M. and Strom, T. B. (1994) New Engl. J. Med. 331:365-375). Accordingly, the formulation of the invention, can be used to inhibit transplant rejection, including rejections of allografts and xenografts and to inhibit GVHD.
  • GVHD graft versus host disease
  • the antibody or antibody portion may be used alone, more preferably it is used in combination with one or more other agents that inhibit the immune response against the allograft or inhibit GVHD.
  • the formulation of the invention is used in combination with OKT3 to inhibit OKT3-induced reactions.
  • the formulation of the invention is used in combination with one or more antibodies directed at other targets involved in regulating immune responses, such as the cell surface molecules CD25 (interleukin-2 receptor- ⁇ ), CD11a (LFA-1), CD54 (ICAM-1), CD4, CD45, CD28/CTLA4, CD80 (B7-1) and/or CD86 (B7-2).
  • the formulation of the invention is used in combination with one or more general immunosuppressive agents, such as cyclosporin A or FK506.
  • Tumor necrosis factor has been implicated in inducing cachexia, stimulating tumor growth, enhancing metastatic potential and mediating cytotoxicity in malignancies (see e.g., Tracey and Cerami, supra).
  • the formulation of the invention can be used in the treatment of malignancies, to inhibit tumor growth or metastasis and/or to alleviate cachexia secondary to malignancy.
  • the formulation may be administered systemically or locally to the tumor site.
  • Tumor necrosis factor has been implicated in the pathophysiology of adult respiratory distress syndrome, including stimulating leukocyte-endothelial activation, directing cytotoxicity to pneumocytes and inducing vascular leakage syndrome (see e.g., Tracey and Cerami, supra).
  • the formulation of the invention can be used to treat various pulmonary disorders, including adult respiratory distress syndrome (see e.g., PCT Publication No. WO 91/04054), shock lung, chronic pulmonary inflammatory disease, pulmonary sarcoidosis, pulmonary fibrosis and silicosis.
  • the formulation may be administered systemically or locally to the lung surface, for example as an aerosol.
  • Tumor necrosis factor has been implicated in the pathophysiology of inflammatory bowel disorders (see e.g., Tracy, K. J., et al. (1986) Science 234:470-474; Sun, X-M., et al. (1988) J. Clin. Invest. 81:1328-1331; MacDonald, T. T., et al. (1990) Clin. Exp. Immunol. 81:301-305).
  • Chimeric murine anti-hTNF ⁇ antibodies have undergone clinical testing for treatment of Crohn's disease (van Dullemen, H. M., et al. (1995) Gastroenterology 109:129-135).
  • the formulation of the invention also can be used to treat intestinal disorders, such as idiopathic inflammatory bowel disease, which includes two syndromes, Crohn's disease and ulcerative colitis.
  • the formulation of the invention also can be used to treat various cardiac disorders, including ischemia of the heart (see e.g., European Patent Application Publication No. EP 453 898) and heart insufficiency (weakness of the heart muscle) (see e.g., PCT Publication No. WO 94/20139).
  • ischemia of the heart see e.g., European Patent Application Publication No. EP 453 898
  • heart insufficiency weakness of the heart muscle
  • the pharmaceutical formulation of the invention also can be used to treat various other disorders in which TNF ⁇ activity is detrimental.
  • diseases and disorders in which TNF ⁇ activity has been implicated in the pathophysiology include inflammatory bone disorders and bone resorption disease (see e.g., Bertolini, D. R., et al. (1986) Nature 319:516-518; Konig, A., et al. (1988) J. Bone Miner. Res. 3:621-627; Lerner, U. H. and Ohlin, A. (1993) J. Bone Miner. Res. 8:147-155; and Shankar, G. and Stern, P. H.
  • hepatitis including alcoholic hepatitis (see e.g., McClain, C. J. and Cohen, D. A. (1989) Hepatology 9:349-35 1; Felver, M. E., et al. (1990) Alcohol. Clin. Exp. Res. 14:255-259; and Hansen, J., et al. (1994) Hepatology 20:461-474) and viral hepatitis (Sheron, N., et al. (1991) J. Hepatol. 12:241-245; and Hussain, M. J., et al. (1994) J. Clin. Pathol.
  • TNF ⁇ activity is detrimental
  • disorders in which TNF ⁇ activity is detrimental include, but are not limited to, adult Still's disease, Alzheimer's disease, ankylosing spondylitis, asthma, cancer and cachexia, atherosclerosis, chronic atherosclerosis, chronic fatigue syndrome, liver failure, chronic liver failure, obstructive pulmonary disease, chronic obstructive pulmonary disease, congestive heart failure, dermatopolymyositis, diabetic macrovasculopathy, endometriosis, familial periodic fevers, fibrosis, hemodialysis, Jarisch-Herxheimer reaction, juvenile RA, Kawasaki syndrome, myelo dysplastic syndrome, myocardial infarction, panciaticular vulgaris, periodontal disease, peripheral neuropathy, polyarticular, polymyositis, progressive renal failure, psoriasis, psoriatic arthritis, Reiter's syndrome, sarcoidosis, scleroderma, spondyloarthropathies, Still
  • Materials which were used in the formulation include: mannitol, citric acid monohydrate (citric acid), sodium citrate, disodium phosphate dihydrate (dibasic sodium phosphate dihydrate), sodium dihydrogen phosphate dihydrate (monobasic sodium phosphate dihydrate), sodium chloride, polysorbate 80, water for the injections, sodium hydroxide, which was used as a 1M solution to adjust the pH, and protein concentrate (e.g., antibody concentrate).
  • a sodium hydroxide solution was prepared by combining 40.0 g of sodium hydroxide with 1000.8 g of water for injections.
  • a buffer was prepared by dissolving the following pre-weighed ingredients (described above) in about 90% of the water for injections: mannitol, citric acid monohydrate, sodium citrate, disodium phosphate dihydrate, sodium dihydrogen phosphate, sodium chloride, and polysorbate 80. It was determined that the sequence of the addition of the buffer constituents was not important and can, therefore, be chosen at will.
  • the pH of the solution was adjusted with 1M sodium hydroxide which was prepared as described above. After the addition of the sodium hydroxide, the final weight of the water was added.
  • the buffer solution was then filtered through a sterilized filter (hydrophilic polyvinylidene difluoride, 0.22 ⁇ m pore size) into a sterilized receptacle.
  • the filtration medium used was filtration sterilized nitrogen.
  • the filtered buffer solution was then added to the thawed and pooled antibody concentrate (the active ingredient of the pharmaceutical formulation), prepared as follows.
  • the antibody (concentrate) was thawed in a water bath prior to the preparation of the pharmaceutical formulation.
  • 34.207 g of antibody concentrate was used, which is equivalent to 2.0 kg of protein with 60 mg protein/mL protein concentrate.
  • the density of the concentrate was 1.0262 g/mL.
  • the buffer was added while stirring, until the final weight of the bulk solution was reached.
  • the formulation was then sterilized by filtration as described above, except the formulation was filtered through two sterile 0.22 ⁇ m membrane filters. Following sterilization, the formulation was packaged for use in either a vial or a pre-filled syringe.
  • weight quantities and/or weight-to-volume ratios recited herein can be converted to moles and/or molarities using the art-recognized molecular weights of the recited ingredients.
  • Weight quantities exemplified herein e.g., g or kg
  • volumes e.g., of buffer or pharmaceutical formulation
  • weight quantities can be proportionally adjusted when different formulation volumes are desired. For example, 32L, 20L, 10L, 5L, or 1L formulations would include 80%, 50%, 25%, 12.5%, or 2.5%, respectively, of the exemplified weight quantities.
  • the drug substance was formulated in the same matrix as the finished product.
  • Table 2 shows that the D2E7 antibody drug substance can be thawed/frozen at least 3 times without any detrimental effect on either chemical (cation exchange HPLC, size exclusion HPLC, colour, pH), physicochemical properties (subvisible particles, clarity) or biological activity (in vitro TNF neutralization assay). Also table 2 shows that the inclusion of polysorbate 80 improved the physicochemical properties of the D2E7 antibody drug substance as evidenced by the lower number of subvisible particles regardless whether a slow or fast freeze/thaw cycle was being used (see shaded areas in table 2).
  • Tests were performed to determine if the formulation can support microbial growth. The results from these experiments showed that the formulation does not support microbial growth if stored at 20 to 25° C. for 14 days. This result was determined by directly inoculating the sterile formulation with microorganisms (e.g., Staphylococous aureus , ATCC-No.: 6538P, Candida albicans , ATCC-No.: 10231 , Aspergillus niger , ATCCC-No.: 16404 , Pseudomonas aeruginosa , ATCC-No.: 9027, an environmental isolate) at low level (NMT 100 cfu/mL).
  • microorganisms e.g., Staphylococous aureus , ATCC-No.: 6538P, Candida albicans , ATCC-No.: 10231 , Aspergillus niger , ATCCC-No.: 16404 , P
  • Inoculated formulations were then examined for overall microbial growth, e.g., for changes in turbidity. A lack of turbidity was an indication of no overall growth, and was detected in the inoculated containers after 14 days. Further, no organisms could be reisolated from these containers. Thus it was concluded that the formulation does not support microbial growth under these conditions.

Abstract

A liquid aqueous pharmaceutical formulation is described which has a high protein concentration, a pH of between about 4 and about 8, and enhanced stability.

Description

    BACKGROUND OF THE INVENTION
  • Tumor necrosis factor α (TNFα) is a cytokine produced by numerous cell types, including monocytes and macrophages, that was originally identified based on its capacity to induce the necrosis of certain mouse tumors (see e.g., Old, L. (1985) [0001] Science 230:630-632). Subsequently, a factor termed cachectin, associated with cachexia, was shown to be the same molecule as TNFα. TNFα has been implicated in mediating shock (see e.g., Beutler, B. and Cerami, A. (1988) Annu. Rev. Biochem. 57:505-518; Beutler, B. and Cerami, A. (1989) Annu. Rev. Immunol. 7:625-655). Furthermore, TNFα has been implicated in the pathophysiology of a variety of other human diseases and disorders, including sepsis, infections, autoimmune diseases, transplant rejection and graft-versus-host disease (see e.g., Moeller, A., et al. (1990) Cytokine 2:162-169; U.S. Pat. No. 5,231,024 to Moeller et al.; European Patent Publication No. 260 610 B1 by Moeller, A., et al. Vasilli, P. (1992) Annu. Rev. Immunol. 10:411-452; Tracey, K. J. and Cerami, A. (1994) Annu. Rev. Med. 45:491-503).
  • Because of the harmful role of human TNFα (hTNFα) in a variety of human disorders, therapeutic strategies have been designed to inhibit or counteract hTNFα activity. In particular, antibodies that bind to, and neutralize, hTNFα have been sought as a means to inhibit hTNFα activity. Some of the earliest of such antibodies were mouse monoclonal antibodies (mAbs), secreted by hybridomas prepared from lymphocytes of mice immunized with hTNFα (see e.g, Hahn T; et al., (1985) [0002] Proc Natl Acad Sci USA 82: 3814-3818; Liang, C-M., et al. (1986) Biochem. Biophys. Res. Commun. 137:847-854; Hirai, M., et al. (1987) J. Immunol. Methods 96:57-62; Fendly, B. M., et al. (1987) Hybridoma 6:359-370; Moeller, A., et al. (1990) Cytokine 2:162-169; U.S. Pat. No. 5,231,024 to Moeller et al.; European Patent Publication No. 186 833 B1 by Wallach, D.; European Patent Application Publication No. 218 868 A1 by Old et al.; European Patent Publication No. 260 610 B1 by Moeller, A., et al.). While these mouse anti-hTNFα antibodies often displayed high affinity for hTNFα (e.g., Kd≦10−9M) and were able to neutralize hTNFα activity, their use in vivo may be limited by problems associated with administration of mouse antibodies to humans, such as short serum half life, an inability to trigger certain human effector functions and elicitation of an unwanted immune response against the mouse antibody in a human (the “human anti-mouse antibody” (HAMA) reaction).
  • In an attempt to overcome the problems associated with use of fully-murine antibodies in humans, murine anti-hTNFα antibodies have been genetically engineered to be more “human-like.” For example, chimeric antibodies, in which the variable regions of the antibody chains are murine-derived and the constant regions of the antibody chains are human-derived, have been prepared (Knight, D. M, et al. (1993) [0003] Mol. Immunol. 30:1443-1453; PCT Publication No. WO 92/16553 by Daddona, P. E., et al.). Additionally, humanized antibodies, in which the hypervariable domains of the antibody variable regions are murine-derived but the remainder of the variable regions and the antibody constant regions are human-derived, have also been prepared (PCT Publication No. WO 92/11383 by Adair, J. R., et al.). However, because these chimeric and humanized antibodies still retain some murine sequences, they still may elicit an unwanted immune reaction, the human anti-chimeric antibody (HACA) reaction, especially when administered for prolonged periods, e.g., for chronic indications, such as rheumatoid arthritis (see e.g., Elliott, M. J., et al. (1994) Lancet 344:1125-1127; Elliot, M. J., et al. (1994) Lancet 344:1105-1110).
  • A preferred hTNFα inhibitory agent to murine mAbs or derivatives thereof (e.g., chimeric or humanized antibodies) would be an entirely human anti-hTNFα antibody, since such an agent should not elicit the HAMA reaction, even if used for prolonged periods. Human monoclonal autoantibodies against hTNFα have been prepared using human hybridoma techniques (Boyle, P., et al. (1993) [0004] Cell. Immunol. 152:556-568; Boyle, P., et al. (1993) Cell. Immunol. 152:569-581; European Patent Application Publication No. 614 984 A2 by Boyle, et al.). However, these hybridoma-derived monoclonal autoantibodies were reported to have an affinity for hTNFα that was too low to calculate by conventional methods, were unable to bind soluble hTNFα and were unable to neutralize hTNFα-induced cytotoxicity (see Boyle, et al.; supra). Moreover, the success of the human hybridoma technique depends upon the natural presence in human peripheral blood of lymphocytes producing autoantibodies specific for hTNFα. Certain studies have detected serum autoantibodies against hTNFα in human subjects (Fomsgaard, A., et al. (1989) Scand. J. Immunol. 30:219-223; Bendtzen, K., et al. (1990) Prog. Leukocyte Biol. 10B:447-452), whereas others have not (Leusch, H-G., et al. (1991) J. Immunol. Methods 139:145-147).
  • Alternative to naturally-occurring human anti-hTNFα antibodies would be a recombinant hTNFα antibody. Recombinant human antibodies that bind hTNFα with relatively low affinity (i.e., K[0005] d˜10−7M) and a fast off rate (i.e., Koff˜10−2 sec−1) have been described (Griffiths, A. D., et al. (1993) EMBO J. 12:725-734). However, because of their relatively fast dissociation kinetics, these antibodies may not be suitable for therapeutic use. Additionally, a recombinant human anti-hTNFα has been described that does not neutralize hTNFα activity, but rather enhances binding of hTNFα to the surface of cells and enhances internalization of hTNFα (Lidbury, A., et al. (1994) Biotechnol. Ther. 5:27-45; PCT Publication No. WO 92/03145 by Aston, R. et al.)
  • Recombinant human antibodies that bind soluble hTNFα with high affinity and slow dissociation kinetics and that have the capacity to neutralize hTNFα activity, including hTNFα-induced cytotoxicity (in vitro and in vivo) and hTNFα-induced cell activation, have also been described (see U.S. Pat. No. 6,090,382). [0006]
    • SUMMARY OF THE INVENTION
  • There is a need for a stable aqueous pharmaceutical formulation with an extended shelf life, comprising an antibody which is suitable for therapeutic use to inhibit or counteract detrimental hTNFα activity. There is also a need for a stable aqueous pharmaceutical formulation with an extended shelf life, comprising an antibody suitable for therapeutic use which is easily administered and contains a high protein concentration. [0007]
  • This invention provides a liquid aqueous pharmaceutical formulation consisting of a therapeutically effective amount of an antibody in a buffered solution forming a formulation having a pH between about 4 and about 8 and having a shelf life of at least 18 months. The invention also includes an aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody in a buffered solution forming a formulation having a pH between about 4 and 8 and having a shelf life of at least 18 months in the liquid state. In one embodiment, the pharmaceutical formulation has enhanced stability. In a further embodiment, the formulation of the invention is stable following at least 3 freeze/thaw cycles of the formulation. In another embodiment, the antibody is directed to TNFα. In yet another embodiment, the antibody is directed to human TNFα. In still another embodiment, the antibody is D2E7. [0008]
  • This invention also provides a liquid aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody in a buffered solution forming a formulation having a pH between 4 and 8 and having enhanced stability of at least 12 months at a temperature of 2-8° C. In one embodiment, the formulation has enhanced stability of at least 18 months. In another embodiment, the antibody is directed to TNFα. In yet another embodiment, the antibody is directed to human TNFα. In a further embodiment, the antibody is D2E7. [0009]
  • The invention further provides a liquid aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody in a buffered solution forming a formulation having a pH between about 4 and about 8 which is easily administratable. In one embodiment, the antibody is directed to TNFα. In yet another embodiment, the antibody is directed to human TNFα. In a further embodiment, the antibody is D2E7. [0010]
  • In one embodiment of the invention, the liquid aqueous pharmaceutical formulation is suitable for injection. In a further embodiment, the formulation is suitable for single use sc injection. In another embodiment, the concentration of the antibody in the liquid aqueous pharmaceutical formulation is about 1-150 mg/ml. In yet another embodiment, the concentration of the antibody in the formulation is about 50 mg/ml. In still another embodiment, the formulation has a high protein concentration. In yet another embodiment of the invention, the formulation is not light sensitive. [0011]
  • In one embodiment of the invention, the liquid aqueous pharmaceutical formulation contains an antibody, or an antigen-binding portion thereof, that dissociates from human TNFα with a K[0012] d of 1×10−8 M or less and a Koff rate constant of 1×10−3 s−1 or less, both determined by surface plasmon resonance, and neutralizes human TNFα cytotoxicity in a standard in vitro L929 assay with an IC50 of 1×10−7 M or less. In another embodiment, the formulation of the invention contains an antibody, or antigen-binding portion thereof, which dissociates from human TNFα with a Koff rate constant of 5×10−4 s−1 or less. In a further embodiment, the formulation contains an antibody, or antigen-binding portion thereof, which dissociates from human TNFα with a Koff rate constant of 1×10−4 s−1 or less. In still a further embodiment, the formulation of the invention contains an antibody, or antigen-binding portion thereof, which neutralizes human TNFα cytotoxicity in a standard in vitro L929 assay with an IC50 of 1×10−8 M or less. In yet another embodiment of the invention, the claimed formulation includes an antibody, or antigen-binding portion thereof, which neutralizes human TNFα cytotoxicity in a standard in vitro L929 assay with an IC50 of 1×10−9 M or less. Another embodiment of the invention, includes a formulation where the antibody, or antigen-binding portion thereof, neutralizes human TNFα cytotoxicity in a standard in vitro L929 assay with an IC50 of 1×10−10 M or less.
  • In another embodiment of the invention, the liquid aqueous pharmaceutical formulation contains of an antibody, or antigen-binding portion thereof, which is a recombinant antibody, or antigen-binding portion thereof. In another embodiment, the formulation contains an antibody, or antigen-binding portion thereof, which inhibits human TNFα-induced expression of ELAM-1 on human umbilical vein endothelial cells. In still another embodiment, the claimed formulation includes the D2E7 antibody. [0013]
  • In another embodiment of the invention, the liquid aqueous pharmaceutical formulation includes an antibody, or antigen-binding portion, thereof which dissociates from human TNFα with a K[0014] off rate constant of 1×10−3 s−1 or less, as determined by surface plasmon resonance;
  • b) has a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9; [0015]
  • c) has a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12. In another embodiment, the formulation of the invention includes an antibody, or an antigen-binding portion thereof, which dissociates from human TNFα with a K[0016] off rate constant of 5×10−4 s−1 or less. In yet another embodiment of the invention, the formulation includes an antibody, or an antigen-binding portion thereof, which dissociates from human TNFα with a Koff rate constant of 1×10−4 s−1 or less.
  • In yet another embodiment of the invention, the liquid aqueous pharmaceutical formulation, contains of an antibody, or antigen-binding portion thereof, which has a light chain variable region (LCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8, and with a heavy chain variable region (HCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11. In a further embodiment, the formulation of the invention contains an antibody, wherein the LCVR of the antibody, or an antigen-binding portion thereof, further has a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5 and the HCVR of the antibody, or an antigen-binding portion thereof, further has a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 6. In yet another embodiment, the formulation of the invention contains an antibody, wherein the LCVR of the antibody, or an antigen-binding portion thereof, further has CDR1 domain comprising the amino acid sequence of SEQ ID NO: 7 and the HCVR has a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 8. [0017]
  • In yet another embodiment of the invention, the antibody or antigen-binding portion thereof, contained in the liquid aqueous pharmaceutical formulation has a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2. In another embodiment, the antibody, or antigen-binding portion thereof, has an IgG1 heavy chain constant region. In still another embodiment, the antibody, or antigen-binding portion thereof, has an IgG4 heavy chain constant region. In another embodiment, the antibody, or antigen-binding portion thereof, is a Fab fragment. In still a further embodiment, the antibody, or antigen-binding portion thereof, is a single chain Fv fragment. [0018]
  • In one embodiment of the invention, the liquid aqueous pharmaceutical formulation, contains an antibody, or antigen-binding portion thereof, which has a light chain variable region (LCVR) having a CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 or with a heavy chain variable region (HCVR) having a CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 34. In still another embodiment, the antibody, or antigen-binding portion thereof, neutralizes the activity of human TNFα, chimpanzee TNFα and at least one additional primate TNFα selected from the group consisting of baboon TNFα, marmoset TNFα, cynomolgus TNFα and rhesus TNFα. In a further embodiment, the formulation of the invention includes an antibody, or an antigen-binding portion thereof, which also neutralizes the activity of mouse TNFα. The formulation of the invention also an antibody, or an antigen-binding portion thereof, which neutralizes the activity of pig TNFα. [0019]
  • In a further embodiment, the invention provides a liquid aqueous pharmaceutical formulation which contains an antibody, or antigen-binding portion thereof, which binds to human TNFα and comprises: [0020]
  • a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9, and [0021]
  • a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12. In one embodiment, the liquid aqueous pharmaceutical formulation includes an antibody which bind human TNFα and comprises a light chain variable region (LCVR) having a CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 or a heavy chain variable region (HCVR) having a CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 34. In a further embodiment of the invention, the antibody, or antigen-binding portion thereof, binds human TNFα and is the antibody D2E7 or an antigen binding portion thereof. [0022]
  • The invention also provides an aqueous pharmaceutical composition comprising a polyol, a surfactant, and a buffer system comprising citrate and/or phosphate with a pH of about 4 to 8, in amounts sufficient to formulate an antibody for therapeutic use at a concentration of greater than about 45 mg/ml. In one embodiment, the polyol is mannitol and the surfactant is polysorbate 80. In another embodiment, the composition includes 5-20 mg/ml of mannitol and 0.1-10 mg/ml of polysorbate 80. In a further embodiment, the composition includes the antibody D2E7. [0023]
  • The invention also provides a liquid aqueous pharmaceutical formulation consisting of 1-150 mg/ml of antibody, 5-20 mg/ml of mannitol, 0.1-10 mg/ml of Tween-80, and a buffer system comprising citrate and/or phosphate, with a pH of 4 to 8. In one embodiment, the antibody is directed to hTNFα. In another embodiment, the formulation contains about 40 mg of antibody. The invention further provides a liquid aqueous pharmaceutical formulation comprising about 50 mg/ml of antibody, about 12 mg/ml of mannitol, about 1 mg/ml of Tween-80, and a buffer system comprising citrate and/or phosphate, with a pH of about 4 to about 8. In one embodiment, the pH of the formulation is between about 4.5 to about 6.0. In another embodiment, the pH is between about 4.8 to about 5.5. In yet another embodiment, the pH of the invention is between about 5.0 to about 5.2. [0024]
  • In one embodiment of the invention, the liquid aqueous pharmaceutical formulation also includes about 1.305 mg/ml of citric acid, about 0.305 mg/ml of sodium citrate, about 1.53 mg/ml of disodium phosphate dihydrate, about 0.86 mg/ml of sodium dihydrogen phosphate dihydrate, and about 6.165 mg/ml of sodium chloride. In another embodiment, the formulation of the invention includes an antibody which is directed to hTNFα. In yet another embodiment, the formulation of the invention includes the antibody D2E7. In yet a further embodiment, the formulation of the invention is administered to a subject suffering from a disorder in which TNFα activity is detrimental such that TNFα activity in the subject is inhibited [0025]
    • DETAILED DESCRIPTION OF THE INVENTION
  • This invention pertains to a liquid aqueous pharmaceutical formulation with a pH of about 4 to about 8 which contains a high protein concentration, including an antibody concentration ranging from about 1 to about 150 mg/ml, and has enhanced stability. This invention also pertains to a liquid aqueous pharmaceutical formulation for therapeutic use in a subject suffering from a condition characterized by detrimental TNFα activity. The formulation of the invention comprises the following constituents: an antibody which binds to human TNFα with high affinity, a low off rate and high neutralizing capacity; a buffer, which includes citric acid, sodium citrate, disodium phosphate dihydrate, and sodium dihydrogen phosphate dihydrate; tonicity agents, which include mannitol and sodium chloride; a detergent, including polysorbate 80; and sodium hydroxide, for pH adjustment. [0026]
  • Definitions [0027]
  • In order that the present invention may be more readily understood, certain terms are first defined. [0028]
  • The term “subject” is intended to include living organisms, e.g., prokaryotes and eukaryotes. Examples of subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In specific embodiments of the invention, the subject is a human. [0029]
  • The term “pharmaceutical formulation” refers to preparations which are in such form as to permit the biological activity of the active ingredients to be unequivocally effective, and which contain no additional components which are significantly toxic to the subjects to which the formulation would be administered. “Pharmaceutically acceptable” excipients (vehicles, additives) are those which can reasonably be administered to a subject mammal to provide an effective dose of the active ingredient employed. [0030]
  • A “stable” formulation is one in which the antibody therein essentially retains its physical stability and/or chemical stability and/or biological activity upon storage. Various analytical techniques for measuring protein stability are available in the art and are reviewed in Peptide and Protein Drug Delivery, 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York, N.Y., Pubs. (1991) and Jones, A. Adv. Drug Delivery Rev. 10: 35 29-90 (1993), for example. Stability can be measured at a selected temperature for a selected time period. Preferably, the formulation is stable at room temperature (about 30° C.) or at 40° C. for at least 1 month and/or stable at about 2-8° C. for at least 1 year for at least 2 years. Furthermore, the formulation is preferably stable following freezing (to, e.g., −70° C.) and thawing of the formulation, hereinafter referred to as a “freeze/thaw cycle.”[0031]
  • An antibody “retains its physical stability” in a pharmaceutical formulation if it shows substantially no signs of aggregation, precipitation and/or denaturation upon visual examination of color and/or clarity, or as measured by UV light scattering or by size exclusion chromatography. [0032]
  • An antibody “retains its chemical stability” in a pharmaceutical formulation, if the chemical stability at a given time is such that the antibody is considered to still retain its biological activity as defined below. Chemical stability can be assessed by detecting and quantifying chemically altered forms of the antibody. Chemical alteration may involve size modification (e.g. clipping) which can be evaluated using size exclusion chromatography, SDS-PAGE and/or matrix-assisted laser desorption ionization/time-of-flight mass spectrometry (MALDI/TOF MS), for example. Other types of chemical alteration include charge alteration (e.g. occurring as a result of deamidation) which can be evaluated by ion-exchange chromatography, for example. [0033]
  • An antibody “retains its biological activity” in a pharmaceutical formulation, if the antibody in a pharmaceutical formulation is biologically active for its intended purpose. For example, biological activity is retained if the biological activity of the antibody in the pharmaceutical formulation is within about 30%, about 20%, or about 10% (within the errors of the assay) of the biological activity exhibited at the time the pharmaceutical formulation was prepared (e.g., as determined in an antigen binding assay). [0034]
  • “Isotonic” is a term recognized in the art. Isotonic can mean, for example, that the formulation of interest has essentially the same osmotic pressure as human blood. Isotonic formulations will generally have an osmotic pressure from about 250 to 350 mOsm. Isotonicity can be measured using a vapor pressure or ice-freezing type osmometer, for example. A “tonicity agent” is a compound which renders the formulation isotonic. [0035]
  • A “polyol” is a substance with multiple hydroxyl groups, and includes sugars (reducing and nonreducing sugars), sugar alcohols and sugar acids. Preferred polyols herein have a molecular weight which is less than about 600 kD (e.g. in the range from about 120 to about 400 kD). A “reducing sugar” is one which contains a hemiacetal group that can reduce metal ions or react covalently with lysine and other amino groups in proteins and a “nonreducing sugar” is one which does not have these properties of a reducing sugar. Examples of reducing sugars are fructose, mannose, maltose, lactose, arabinose, xylose, ribose, rhamnose, galactose and glucose. Nonreducing sugars include sucrose, trehalose, sorbose, melezitose and raffinose. Mannitol, xylitol, erythritol, threitol, sorbitol and glycerol are examples of sugar alcohols. As to sugar acids, these include L-gluconate and metallic salts thereof. Where it desired that the formulation is freeze-thaw stable, the polyol is preferably one which does not crystallize at freezing temperatures (e.g. −20° C.) such that it destabilizes the antibody in the formulation. The polyl may also act as a tonicity agent. In one embodiment of the invention, one ingredient of the formulation is mannitol in a concentration of 5 to 20 mg/ml. In a preferred embodiment of the invention, the concentration of mannitol is 7.5 to 15 mg/ml. In a more preferred embodiment of the invention, the concentration of mannitol is 10-14 mg/ml. [0036]
  • As used herein, “buffer” refers to a buffered solution that resists changes in pH by the action of its acid-base conjugate components. The buffer of this invention has a pH in the range from about 4 to about 8; preferably from about 4.5 to about 7; and most preferably has a pH in the range from about 5.0 to about 6.5. Examples of buffers that will control the pH in this range include acetate (e.g. sodium acetate), succinate (such as sodium succinate), gluconate, histidine, citrate and other organic acid buffers. [0037]
  • In a pharmacological sense, in the context of the present invention, a “therapeutically effective amount” or “effective amount” of an antibody refers to an amount effective in the prevention or treatment of a disorder for the treatment of which the antibody is effective. A “disorder” is any condition that would benefit from treatment with the antibody. This includes chronic and acute disorders or diseases including those pathological conditions which predisposes the subject to the disorder in question. [0038]
  • A “preservative” is a compound which can be included in the formulation to essentially reduce bacterial action therein, thus facilitating the production of a multi-use formulation, for example. Examples of potential preservatives include octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride (a mixture of alkylbenzyldimethylammonium chlorides in which the alkyl groups are long-chain compounds), and benzethonium chloride. Other types of preservatives include aromatic alcohols such as phenol, butyl and benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol. [0039]
  • “Treatment” refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disorder as well as those in which the disorder is to be prevented. [0040]
  • The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. [0041]
  • The phrases “systemic administration,” “administered systemically,” “peripheral administration” and “administered peripherally” as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration. [0042]
  • The phrase “pharmaceutically acceptable carrier” is art recognized and includes a pharmaceutically acceptable material, composition or vehicle, suitable for administration to mammals. The carriers include liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. [0043]
  • The term “human TNFα” (abbreviated herein as hTNFα, or simply hTNF), as used herein, is intended to refer to a human cytokine that exists as a 17 kD secreted form and a 26 kD membrane associated form, the biologically active form of which is composed of a trimer of noncovalently bound 17 kD molecules. The structure of hTNFα is described further in, for example, Pennica, D., et al. (1984) [0044] Nature 312:724-729; Davis, J. M., et al. (1987) Biochemistry 26:1322-1326; and Jones, E. Y., et al. (1989) Nature 338:225-228. The term human TNFα is intended to include recombinant human TNFα (rhTNFα), which can be prepared by standard recombinant expression methods or purchased commercially (R & D Systems, Catalog No. 210-TA, Minneapolis, Minn.).
  • The term “antibody”, as used herein, is intended to refer to immunoglobulin molecules comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In one embodiment of the invention, the formulation contains an antibody with CDR1, CDR2, and CDR3 sequences like those described in U.S. Pat. Nos. 6,090,382 and 6,258,562, each incorporated by reference herein. [0045]
  • The term “antigen-binding portion” of an antibody (or simply “antibody portion”), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., hTNFα). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed within the term “antigen-binding portion” of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) a F(ab′)[0046] 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., (1989) Nature 341:544-546 ), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single chain antibodies are also intended to be encompassed within the term “antigen-binding portion” of an antibody. Other forms of single chain antibodies, such as diabodies are also encompassed. Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites (see e.g., Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, R. J., et al. (1994) Structure 2:1121-1123). In one embodiment of the invention, the formulation contains an antigen-binding portions described in U.S. Pat. Nos. 6,090,382 and 6,258,562, each incorporated by reference herein.
  • Still further, an antibody or antigen-binding portion thereof may be part of a larger immunoadhesion molecules, formed by covalent or noncovalent association of the antibody or antibody portion with one or more other proteins or peptides. Examples of such immunoadhesion molecules include use of the streptavidin core region to make a tetrameric scFv molecule (Kipriyanov, S. M., et al. (1995) [0047] Human Antibodies and Hybridomas 6:93- 101) and use of a cysteine residue, a marker peptide and a C-terminal polyhistidine tag to make bivalent and biotinylated scFv molecules (Kipriyanov, S. M., et al. (1994) Mol. Immunol. 31:1047-1058). Antibody portions, such as Fab and F(ab′)2 fragments, can be prepared from whole antibodies using conventional techniques, such as papain or pepsin digestion, respectively, of whole antibodies. Moreover, antibodies, antibody portions and immunoadhesion molecules can be obtained using standard recombinant DNA techniques, as described herein.
  • The term “human antibody”, as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3. However, the term “human antibody”, as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. [0048]
  • The term “recombinant human antibody”, as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further in Section II, below), antibodies isolated from a recombinant, combinatorial human antibody library (described further in Section III, below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor, L. D., et al. (1992) [0049] Nucl. Acids Res. 20:6287-6295) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
  • An “isolated antibody”, as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds hTNFα is substantially free of antibodies that specifically bind antigens other than hTNFα. An isolated antibody that specifically binds hTNFα may, however, have cross-reactivity to other antigens, such as TNFα molecules from other species. Moreover, an isolated antibody may be substantially free of other cellular material and/or chemicals. [0050]
  • A “neutralizing antibody”, as used herein (or an “antibody that neutralized hTNFα activity”), is intended to refer to an antibody whose binding to hTNFα results in inhibition of the biological activity of hTNFα. This inhibition of the biological activity of hTNFα can be assessed by measuring one or more indicators of hTNFα biological activity, such as hTNFα-induced cytotoxicity (either in vitro or in vivo), hTNFα-induced cellular activation and hTNFα binding to hTNFα receptors. These indicators of hTNFα biological activity can be assessed by one or more of several standard in vitro or in vivo assays known in the art, and described in U.S. Pat. Nos. 6,090,382 and 6,258,562, each incorporated by reference herein. Preferably, the ability of an antibody to neutralize hTNFα activity is assessed by inhibition of hTNFα-induced cytotoxicity of L929 cells. As an additional or alternative parameter of hTNFα activity, the ability of an antibody to inhibit hTNFα-induced expression of ELAM-1 on HUVEC, as a measure of hTNFα-induced cellular activation, can be assessed. [0051]
  • The term “surface plasmon resonance”, as used herein, refers to an optical phenomenon that allows for the analysis of real-time biospecific interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIAcore system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.). For further descriptions, see Jönsson, U., et al. (1993) [0052] Ann. Biol. Clin. 51:19-26; Jönsson, U., et al. (1991) Biotechniques 11:620-627; Johnsson, B., et al. (1995) J. Mol. Recognit. 8:125-131; and Johnnson, B., et al. (1991) Anal. Biochem. 198:268-277.
  • The term “K[0053] off”, as used herein, is intended to refer to the off rate constant for dissociation of an antibody from the antibody/antigen complex.
  • The term “K[0054] d”, as used herein, is intended to refer to the dissociation constant of a particular antibody-antigen interaction.
  • II. Antibodies of the Formulation [0055]
  • The invention is directed to a liquid aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody in a buffered solution forming a formulation having a pH between about 4 and about 8 and having an extended shelf life, preferably of at least about 18 months. In another embodiment, the liquid aqueous pharmaceutical formulation of the invention has enhanced stability. In a further embodiment of the invention, the formulation is not light sensitive. In yet another embodiment of the invention, the claimed formulation remains stable following at least 3 freeze/thaw cycles. In still another embodiment, the pharmaceutical formulation of the invention is suitable for single use sc injection. [0056]
  • Antibodies that can be used in the formulation include polyclonal, monoclonal, recombinant antibodies, single chain antibodies, hybrid antibodies, chimeric antibodies, humanized antibodies, or fragments thereof. Antibody-like molecules containing one or two binding sites for an antigen and a Fc-part of an immunoglobulin can also be used. An example of an antibody-like molecule is the active ingredient etanercept or infliximab. Preferred antibodies used in the formulation are human antibodies which are cloned from human cells or from gene-archives representing the human antibody-reservoir. Especially preferred among the human antibodies are antibodies directed against the antigen TNFα, including human TNFα (or hTNFα). [0057]
  • In one embodiment, the formulation of the invention includes a combination of antibodies (two or more), or a “cocktail” of antibodies. For example, the formulation can include the antibody D2E7 and one or more additional antibodies. [0058]
  • In a preferred embodiment of the invention, the formulation contains an antibody, or antigen-binding portion thereof, dissociates from human TNFα with a K[0059] d of 1×10−8 M or less and a Koff rate constant of 1×10−3 s−1 or less, both determined by surface plasmon resonance, and neutralizes human TNFα cytotoxicity in a standard in vitro L929 assay with an IC50 of 1×10−7 M or less. In another preferred embodiment, the formulation of the invention contains an antibody, or antigen-binding portion thereof, like those described in U.S. Pat. Nos. 6,090,382 and 6,258,562, each incorporated by reference herein.
  • In one aspect, the formulation of the invention contains D2E7 antibodies and antibody portions, D2E7-related antibodies and antibody portions, and other human antibodies and antibody portions with equivalent properties to D2E7, such as high affinity binding to hTNFα with low dissociation kinetics and high neutralizing capacity. In another one embodiment, the formulation of the invention contains an isolated human antibody, or an antigen-binding portion thereof, that dissociates from human TNFα with a K[0060] d of 1×10−8 M or less and a Koff rate constant of 1×10−3 s−1 or less, both determined by surface plasmon resonance, and neutralizes human TNFα cytotoxicity in a standard in vitro L929 assay with an IC50 of 1×10−7 M or less. More preferably, the isolated human antibody, or antigen-binding portion thereof, dissociates from human TNFα with a Koff of 5×10−4 s−1 or less, or even more preferably, with a Koff of 1×10−4 s−1 or less. More preferably, the isolated human antibody, or antigen-binding portion thereof, neutralizes human TNFα cytotoxicity in a standard in vitro L929 assay with an IC50 of 1×10−8 M or less, even more preferably with an IC50 of 1×10−9 M or less and still more preferably with an IC50 of 5×10−10 M or less. In a preferred embodiment, the formulation contains an antibody which is an isolated human recombinant antibody, or an antigen-binding portion thereof. In another preferred embodiment, the formulation contains an antibody which also neutralizes TNFα-induced cellular activation, as assessed using a standard in vitro assay for TNFα-induced ELAM-1 expression on human umbilical vein endothelial cells (HUVEC).
  • III. Preparation of Formulation [0061]
  • The present invention features formulations (e.g., protein formulations and/or antibody formulations) having improved properties as compared to art-recognized formulations. For example, the formulations of the invention have an improved shelf life and/or stability as compared to art recognized formulations. In a preferred aspect, the formulations of the invention comprise a high protein concentration, including, for example, a protein concentration greater than about 45 mg/ml, a protein concentration greater than about 50 mg/ml, a protein concentration greater than about 100 mg/ml, or a protein concentration greater than about 150 mg/ml. In a preferred embodiment of the invention, the protein is an antibody. In another preferred embodiment, the antibody is D2E7. The invention also provides an aqueous pharmaceutical composition comprising a polyol, a surfactant, and a buffer system comprising citrate and/or phosphate with a pH of about 4 to 8, in amounts sufficient to formulate an antibody for therapeutic use at a concentration of greater than about, for example, 45 mg/ml. [0062]
  • Preparation of the antibody of interest is performed according to standard methods known in the art. In a preferred embodiment of the invention, the antibody used in the formulation is expressed in CHO cells and purified by a standard series of chromatography steps. In a further preferred embodiment, the antibody is directed to hTNFα, and is prepared according to the methods described in U.S. Pat. Nos. 6,090,382 and 6,258,562, each incorporated by reference herein. [0063]
  • After preparation of the antibody of interest, the pharmaceutical formulation comprising the antibody is prepared. The therapeutically effective amount of antibody present in the formulation is determined, for example, by taking into account the desired dose volumes and mode(s) of administration. In one embodiment of the invention, the concentration of the antibody in the formulation is between about 1 to about 150 mg of antibody per ml of liquid formulation. In a preferred embodiment, the concentration of the antibody in the formulation is between about 5 to about 80 mg per ml. In another preferred embodiment, the concentration of the antibody in the formulation is between about 25 to about 50 mg/ml. The formulation is especially suitable for large antibody dosages of more than 15 mg/ml. In a preferred embodiment, the concentration of the antibody is 50 mg/ml. [0064]
  • In another embodiment of the invention, the concentration of the antibody in the formulation is about 1-150 mg/ml, about 5-145 mg/ml, about 10-140 mg/ml, about 15-135 mg/ml, about 20-130 mg/ml, about 25-125 mg/ml, about 30-120 mg/ml, about 35-115 mg/ml, about 40-110 mg/ml, about 45-105 mg/ml, about 50-100 mg/ml, about 55-95 mg/ml, about 60-90 mg/ml, about 65-85 mg/ml, about 70-80 mg/ml, or about 75 mg/ml. Ranges intermediate to the above recited concentrations, e.g., about 6-144 mg/ml, are also intended to be part of this invention. For example, ranges of values using a combination of any of the above recited values as upper and/or lower limits are intended to be included. [0065]
  • In one embodiment, the invention provides a formulation with an extended shelf life comprising of an active ingredient, preferably an antibody, in combination with mannitol, citric acid monohydrate, sodium citrate, disodium phosphate dihydrate, sodium dihydrogen phosphate dihydrate, sodium chloride, polysorbate 80, water, and sodium hydroxide. In a further embodiment, the formulation of the invention has an extended shelf life of at least about 18 months in the liquid state. Freezing the formulation of the invention can also be used to further extend its shelf life. [0066]
  • An aqueous formulation is prepared comprising the antibody in a pH-buffered solution. The buffer of this invention has a pH ranging from about 4 to about 8, preferably from about 4.5 to about 6.0, more preferably from about 4.8 to about 5.5, and most preferably has a pH of about 5.0 to about 5.2. Ranges intermediate to the above recited pH's are also intended to be part of this invention. For example, ranges of values using a combination of any of the above recited values as upper and/or lower limits are intended to be included. Examples of buffers that will control the pH within this range include acetate (e.g. sodium acetate), succinate (such as sodium succinate), gluconate, histidine, citrate and other organic acid buffers. [0067]
  • In a preferred embodiment of the invention, the formulation comprises a buffer system which contains citrate and phosphate to maintain the pH in a range of about 4 to about 8. In a further preferred embodiment the pH range is from about 4.5 to about 6.0, more preferably from about pH 4.8 to about 5.5, and most preferably in a pH range of about 5.0 to about 5.2. In another preferred embodiment, the buffer system includes citric acid monohydrate, sodium citrate, disodium phosphate dihydrate, and/or sodium dihydrogen phosphate dihydrate. In a further preferred embodiment, the buffer system includes about 1.3 mg/ml of citric acid (e.g., 1.305 mg/ml), about 0.3 mg/ml of sodium citrate (e.g., 0.305 mg/ml), about 1.5 mg/ml of disodium phosphate dihydrate (e.g. 1.53 mg/ml), about 0.9 mg/ml of sodium dihydrogen phosphate dihydrate (e.g., 0.86), and about 6.2 mg/ml of sodium chloride (e.g., 6.165 mg/ml). In additional preferred embodiments, the buffer system includes 1-1.5 mg/ml of citric acid, 0.25 to 0.5 mg/ml of sodium citrate, 1.25 to 1.75 mg/ml of of disodium phosphate dihydrate, 0.7 to 1.1 mg/ml of sodium dihydrogen phosphate dihydrate, and 6.0 to 6.4 mg/ml of sodium chloride. In a further embodiment, the pH of the formulation is adjusted with sodium hydroxide. [0068]
  • A polyol, which acts as a tonicifier and may stabilize the antibody, is also included in the formulation. The polyol is added to the formulation in an amount which may vary with respect to the desired isotonicity of the formulation. Preferably the aqueous formulation is isotonic. The amount of polyol added may also alter with respect to the molecular weight of the polyol. For example, a lower amount of a monosaccharide (e.g. mannitol) may be added, compared to a disaccharide (such as trehalose). In a preferred embodiment of the invention, the polyol which is used in the formulation as a tonicity agent is mannitol. In a preferred embodiment of the invention, the mannitol concentration is about 5 to 20 mg/ml. In another preferred embodiment of the invention, the concentration of mannitol is about 7.5 to 15 mg/ml. In a more preferred embodiment of the formulation of the invention, the concentration of mannitol is about 10-14 mg/ml. In the most preferred embodiment, the concentration of mannitol is about 12 mg/ml. In another embodiment of the invention, the polyol sorbitol is included in the formulation. [0069]
  • A detergent or surfactant is also added to the antibody formulation. Exemplary detergents include nonionic detergents such as polysorbates (e.g. polysorbates 20, 80 etc) or poloxamers (e.g. poloxamer 188). The amount of detergent added is such that it reduces aggregation of the formulated antibody and/or minimizes the formation of particulates in the formulation and/or reduces adsorption. In a preferred embodiment of the invention, the formulation includes a surfactant which is a polysorbate. In another preferred embodiment of the invention, the formulation contains the detergent polysorbate 80 or Tween 80. Tween 80 is a term used to describe polyoxyethylene (20) sorbitanmonooleate (see Fiedler, Lexikon der Hifsstoffe, Editio Cantor Verlag Aulendorf, 4th edi., 1996). In one preferred embodiment, the formulation contains between about 0.1 and about 10 mg/ml of polysorbate 80, more preferably between about 0.5 and about 5 mg/ml. In another preferred embodiment, about 0.1% polysorbate 80 is found in the formulation of the invention. [0070]
  • In a preferred embodiment of the invention, the formulation is a 0.8 mL solution in a vial containing the ingredients shown below in Table 1. [0071]
    TABLE 1
    1 vial with 0.8 mL solution for injection1) contains:
    Name of ingredient Quantity Function
    Active substance:
    Antibody (D2E7)2) 40.0 mg Active substance
    Excipients:
    Mannitol 9.6 mg Tonicity agent
    Citric acid monohydrate 1.044 mg Buffer
    Citric acid
    Sodium citrate 0.244 mg Buffer
    Sodium citrate
    Disodium phosphate 1.224 mg Buffer
    dihydrate
    Dibasic sodium phosphate
    dihydrate
    Sodium dihydrogen 0.688 mg Buffer
    phosphate dihydrate
    Monobasic sodium
    phosphate dihydrate
    Sodium chloride 4.932 mg Tonicity agent
    Polysorbate 80 0.8 mg Detergent
    Water for injections 759.028-759.048 mg Solvent
    Water for injection
    Sodium hydroxide3) 0.02-0.04 mg pH adjustment
    Total 817.6 mg
  • In one embodiment, the formulation contains the above-identified agents (i.e. antibody, buffer, polyol and detergent) and is essentially free of one or more preservatives, such as benzyl alcohol, phenol, m-cresol, chlorobutanol and benzethonium Cl. In another embodiment, a preservative may be included in the formulation, particularly where the formulation is a multidose formulation. One or more other pharmaceutically acceptable carriers, excipients or stabilizers such as those described in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980) may be included in the formulation provided that they do not significantly adversely affect the desired characteristics of the formulation. Acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed and include; additional buffering agents; co-solvents; antioxidants including ascorbic acid and methionine; chelating agents such as EDTA; metal complexes (e.g. Zn-protein complexes); biodegradable polymers such as polyesters; and/or salt-forming counterions such as sodium. [0072]
  • The formulation herein may also be combined with one or more other therapeutic agents as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect the antibody of the formulation. Such therapeutic agents are suitably present in combination in amounts that are effective for the purpose intended. Additional therapeutic agents which can be combined with the formulation of the invention are further described in U.S. Pat. Nos. 6,090,382 and 6,258,562, each of which is incorporated herein by reference. [0073]
  • The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes, prior to, or following, preparation of the formulation. [0074]
  • IV. Administration of Formulation [0075]
  • The formulation of the invention can be used in similar indications as those described in U.S. Pat. Nos. 6,090,382 and 6,258,562, each incorporated by reference herein, and further detailed below. [0076]
  • The language “effective amount” of the formulation is that amount necessary or sufficient to inhibit TNFα activity, e.g., prevent the various morphological and somatic symptoms of a detrimental TNFα activity-associated state. In another embodiment, the effective amount of the formulation is the amount necessary to achieve the desired result. In one example, an effective amount of the formulation is the amount sufficient to inhibit detrimental TNFα activity. In another example, an effective amount of the formulation is 0.8 mL of the formulation containing 40 mg of antibody, as described in table 1. The effective amount can vary depending on such factors as the size and weight of the subject, or the type of illness. For example, the choice of a TNFα activity-inhibiting formulation can affect what constitutes an “effective amount”. One of ordinary skill in the art would be able to study the aforementioned factors and make the determination regarding the effective amount of the TNFα activity inhibiting formulation without undue experimentation. [0077]
  • The regimen of administration can affect what constitutes an effective amount. The TNFα activity-inhibiting formulation can be administered to the subject either prior to or after the onset of detrimental TNFα activity. Further, several divided dosages, as well as staggered dosages, can be administered daily or sequentially, or the dose can be continuously infused, or can be a bolus injection. Further, the dosages of the TNFα activity-inhibiting formulation can be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation. [0078]
  • The term “treated,” “treating” or “treatment” includes the diminishment or alleviation of at least one symptom associated or caused by the state, disorder or disease being treated. For example, treatment can be diminishment of one or several symptoms of a disorder or complete eradication of a disorder. [0079]
  • Actual dosage levels of the active ingredients (antibody) in the pharmaceutical formulation of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. [0080]
  • The selected dosage level will depend upon a variety of factors including the activity of the antibody found in the formulation, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. [0081]
  • A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition of the present invention required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical formulation at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. [0082]
  • In general, a suitable daily dose of a formulation of the invention will be that amount of the formulation that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. An effective amount of the formulation of the present invention is an amount that inhibits TNFα activity in a subject suffering from a disorder in which TNFα activity is detrimental. In a preferred embodiment, the formulation provides an effective dose of 40 mg per injection of the active ingredient, the antibody. In another embodiment, the formulation provides an effective dose which ranges from about 1 to 150 mg of antibody. If desired, the effective daily dose of the pharmaceutical formulation may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. [0083]
  • In one embodiment of the invention, the dosage of the antibody in the formulation is between about 5 to about 80 mg. In another embodiment, the dosage of the antibody in the formulation is between about 25 to about 50 mg. The formulation is especially suitable for large antibody dosages of more than 15 mg. In a preferred embodiment of the invention, the formulation provides an antibody at a dose of about 40 mg. In another preferred embodiment, the antibody is directed to TNFα. In the most preferred embodiment, the antibody is D2E7. [0084]
  • In one embodiment of the invention, the dosage of the antibody in the formulation is between about 1-150 mg, about 5-145 mg, about 10-140 mg, about 15-135 mg, about 20-130 mg, about 25-125 mg, about 30-120 mg, about 35-115 mg, about 40-110 mg, about 45-105 mg, about 50-100 mg, about 55-95 mg, about 60-90 mg, about 65-85 mg, about 70-80 mg, or about 75 mg. In a preferred embodiment, the dosage of the antibody is 40 mg. In a further preferred embodiment, the antibody is directed to TNFα. In the most preferred embodiment, the antibody is D2E7. Ranges intermediate to the above recited dosages, e.g., about 2-149 mg, are also intended to be part of this invention. For example, ranges of values using a combination of any of the above recited values as upper and/or lower limits are intended to be included. [0085]
  • It is to be noted that dosage values may vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. [0086]
  • The invention provides a pharmaceutical formulation with an extended shelf life, which, in one embodiment, is used to inhibit TNFα activity in a subject suffering from a disorder in which TNFα activity is detrimental, comprising administering to the subject an antibody or antibody portion of the invention such that TNFα activity in the subject is inhibited. Preferably, the TNFα is human TNFα and the subject is a human subject. Alternatively, the subject can be a mammal expressing a TNFα with which an antibody of the invention cross-reacts. Still further the subject can be a mammal into which has been introduced hTNFα (e.g., by administration of hTNFα or by expression of an hTNFα transgene). A formulation of the invention can be administered to a human subject for therapeutic purposes (discussed further below). In one embodiment of the invention, the liquid pharmaceutical formulation is easily administratable, which includes, for example, a formulation which is self-administered by the patient. In a preferred embodiment, the formulation of the invention is administered through sc injection, preferably single use. Moreover, a formulation of the invention can be administered to a non-human mammal expressing a TNFα with which the antibody cross-reacts (e.g., a primate, pig or mouse) for veterinary purposes or as an animal model of human disease. Regarding the latter, such animal models may be useful for evaluating the therapeutic efficacy of antibodies of the invention (e.g., testing of dosages and time courses of administration). [0087]
  • As used herein, the term “a disorder in which TNFα activity is detrimental” is intended to include diseases and other disorders in which the presence of TNFα in a subject suffering from the disorder has been shown to be or is suspected of being either responsible for the pathophysiology of the disorder or a factor that contributes to a worsening of the disorder. Accordingly, a disorder in which TNFα activity is detrimental is a disorder in which inhibition of TNFα activity is expected to alleviate the symptoms and/or progression of the disorder. Such disorders may be evidenced, for example, by an increase in the concentration of TNFα in a biological fluid of a subject suffering from the disorder (e.g., an increase in the concentration of TNFα in serum, plasma, synovial fluid, etc. of the subject), which can be detected, for example, using an anti-TNFα antibody as described above. [0088]
  • There are numerous examples of disorders in which TNFα activity is detrimental. Examples of disorders in which TNFα activity is detrimental are described in U.S. application Ser. No. 60/397275, incorporated by reference herein. Examples in which TNFα activity is detrimental are also described in U.S. Pat. Nos. 6,015,557, 6,177,077, 6,379,666, 6,419,934, 6,419,944, 6,423,321, and 6,428,787; U.S. patent application Ser. Nos. US2001/0016195, US2001/0004456, and US2001/026801; WO 00/50079 and WO 01/49321, each incorporated by reference herein. [0089]
  • The use of the antibodies and antibody portions of the invention in the treatment of specific disorders is discussed further below: [0090]
  • A. Sepsis [0091]
  • Tumor necrosis factor has an established role in the pathophysiology of sepsis, with biological effects that include hypotension, myocardial suppression, vascular leakage syndrome, organ necrosis, stimulation of the release of toxic secondary mediators and activation of the clotting cascade (see e.g., Tracey, K. J. and Cerami, A. (1994) [0092] Annu. Rev. Med. 45:491-503; Russell, D and Thompson, R. C. (1993) Curr. Opin. Biotech. 4:714-721). Accordingly, the formulation of the invention can be used to treat sepsis in any of its clinical settings, including septic shock, endotoxic shock, gram negative sepsis and toxic shock syndrome.
  • Furthermore, to treat sepsis, the formulation of the invention can be coadministered with one or more additional therapeutic agents that may further alleviate sepsis, such as an interleukin-1 inhibitor (such as those described in PCT Publication Nos. WO 92/16221 and WO 92/17583), the cytokine interleukin-6 (see e.g., PCT Publication No. WO 93/11793) or an antagonist of platelet activating factor (see e.g., European Patent Application Publication No. EP 374 510). [0093]
  • Additionally, in a preferred embodiment, the formulation of the invention is administered to a human subject within a subgroup of sepsis patients having a serum or plasma concentration of IL-6 above 500 pg/ml, and more preferably 1000 pg/ml, at the time of treatment (see PCT Publication No. WO 95/20978 by Daum, L., et al.). [0094]
  • B. Autoimmune Diseases [0095]
  • Tumor necrosis factor has been implicated in playing a role in the pathophysiology of a variety of autoimmune diseases. For example, TNFα has been implicated in activating tissue inflammation and causing joint destruction in rheumatoid arthritis (see e.g., Tracey and Cerami, supra; Arend, W. P. and Dayer, J-M. (1995) [0096] Arth. Rheum. 38:151-160; Fava, R. A., et al. (1993) Clin. Exp. Immunol. 94:261-266). TNFα also has been implicated in promoting the death of islet cells and in mediating insulin resistance in diabetes (see e.g., Tracey and Cerami, supra; PCT Publication No. WO 94/08609). TNFα also has been implicated in mediating cytotoxicity to oligodendrocytes and induction of inflammatory plaques in multiple sclerosis (see e.g., Tracey and Cerami, supra). Chimeric and humanized murine anti-hTNFα antibodies have undergone clinical testing for treatment of rheumatoid arthritis (see e.g., Elliott, M. J., et al. (1994) Lancet 344:1125-1127; Elliot, M. J., et al. (1994) Lancet 344:1105-1110; Rankin, E. C., et al. (1995) Br. J. Rheumatol. 34:334-342).
  • The formulation of the invention can be used to treat autoimmune diseases, in particular those associated with inflammation, including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and gouty arthritis, allergy, multiple sclerosis, autoimmune diabetes, autoimmune uveitis and nephrotic syndrome. Typically, the formulation is administered systemically, although for certain disorders, local administration of the antibody or antibody portion at a site of inflammation may be beneficial (e.g., local administration in the joints in rheumatoid arthritis or topical application to diabetic ulcers, alone or in combination with a cyclohexane-ylidene derivative as described in PCT Publication No. WO 93/19751). [0097]
  • C. Infectious Diseases [0098]
  • Tumor necrosis factor has been implicated in mediating biological effects observed in a variety of infectious diseases. For example, TNFα has been implicated in mediating brain inflammation and capillary thrombosis and infarction in malaria (see e.g., Tracey and Cerami, supra). TNFα also has been implicated in mediating brain inflammation, inducing breakdown of the blood-brain barrier, triggering septic shock syndrome and activating venous infarction in meningitis (see e.g., Tracey and Cerami, supra). TNFα also has been implicated in inducing cachexia, stimulating viral proliferation and mediating central nervous system injury in acquired immune deficiency syndrome (AIDS) (see e.g., Tracey and Cerami, supra). Accordingly, the antibodies, and antibody portions, of the invention, can be used in the treatment of infectious diseases, including bacterial meningitis (see e.g., European Patent Application Publication No. EP 585 705), cerebral malaria, AIDS and AIDS-related complex (ARC) (see e.g., European Patent Application Publication No. EP 230 574), as well as cytomegalovirus infection secondary to transplantation (see e.g., Fietze, E., et al. (1994) [0099] Transplantation 58:675-680). The formulation of the invention, also can be used to alleviate symptoms associated with infectious diseases, including fever and myalgias due to infection (such as influenza) and cachexia secondary to infection (e.g., secondary to AIDS or ARC).
  • D. Transplantation [0100]
  • Tumor necrosis factor has been implicated as a key mediator of allograft rejection and graft versus host disease (GVHD) and in mediating an adverse reaction that has been observed when the rat antibody OKT3, directed against the T cell receptor CD3 complex, is used to inhibit rejection of renal transplants (see e.g., Tracey and Cerami, supra; Eason, J. D., et al. (1995) [0101] Transplantation 59:300-305; Suthanthiran, M. and Strom, T. B. (1994) New Engl. J. Med. 331:365-375). Accordingly, the formulation of the invention, can be used to inhibit transplant rejection, including rejections of allografts and xenografts and to inhibit GVHD. Although the antibody or antibody portion may be used alone, more preferably it is used in combination with one or more other agents that inhibit the immune response against the allograft or inhibit GVHD. For example, in one embodiment, the formulation of the invention is used in combination with OKT3 to inhibit OKT3-induced reactions. In another embodiment, the formulation of the invention is used in combination with one or more antibodies directed at other targets involved in regulating immune responses, such as the cell surface molecules CD25 (interleukin-2 receptor-α), CD11a (LFA-1), CD54 (ICAM-1), CD4, CD45, CD28/CTLA4, CD80 (B7-1) and/or CD86 (B7-2). In yet another embodiment, the formulation of the invention is used in combination with one or more general immunosuppressive agents, such as cyclosporin A or FK506.
  • E. Malignancy [0102]
  • Tumor necrosis factor has been implicated in inducing cachexia, stimulating tumor growth, enhancing metastatic potential and mediating cytotoxicity in malignancies (see e.g., Tracey and Cerami, supra). Accordingly, the formulation of the invention, can be used in the treatment of malignancies, to inhibit tumor growth or metastasis and/or to alleviate cachexia secondary to malignancy. The formulation may be administered systemically or locally to the tumor site. [0103]
  • F. Pulmonary Disorders [0104]
  • Tumor necrosis factor has been implicated in the pathophysiology of adult respiratory distress syndrome, including stimulating leukocyte-endothelial activation, directing cytotoxicity to pneumocytes and inducing vascular leakage syndrome (see e.g., Tracey and Cerami, supra). Accordingly, the formulation of the invention, can be used to treat various pulmonary disorders, including adult respiratory distress syndrome (see e.g., PCT Publication No. WO 91/04054), shock lung, chronic pulmonary inflammatory disease, pulmonary sarcoidosis, pulmonary fibrosis and silicosis. The formulation may be administered systemically or locally to the lung surface, for example as an aerosol. [0105]
  • G. Intestinal Disorders [0106]
  • Tumor necrosis factor has been implicated in the pathophysiology of inflammatory bowel disorders (see e.g., Tracy, K. J., et al. (1986) [0107] Science 234:470-474; Sun, X-M., et al. (1988) J. Clin. Invest. 81:1328-1331; MacDonald, T. T., et al. (1990) Clin. Exp. Immunol. 81:301-305). Chimeric murine anti-hTNFα antibodies have undergone clinical testing for treatment of Crohn's disease (van Dullemen, H. M., et al. (1995) Gastroenterology 109:129-135). The formulation of the invention, also can be used to treat intestinal disorders, such as idiopathic inflammatory bowel disease, which includes two syndromes, Crohn's disease and ulcerative colitis.
  • H. Cardiac Disorders [0108]
  • The formulation of the invention, also can be used to treat various cardiac disorders, including ischemia of the heart (see e.g., European Patent Application Publication No. EP 453 898) and heart insufficiency (weakness of the heart muscle) (see e.g., PCT Publication No. WO 94/20139). [0109]
  • I. Others [0110]
  • The pharmaceutical formulation of the invention, also can be used to treat various other disorders in which TNFα activity is detrimental. Examples of other diseases and disorders in which TNFα activity has been implicated in the pathophysiology, and thus which can be treated using the formulation of the invention, include inflammatory bone disorders and bone resorption disease (see e.g., Bertolini, D. R., et al. (1986) [0111] Nature 319:516-518; Konig, A., et al. (1988) J. Bone Miner. Res. 3:621-627; Lerner, U. H. and Ohlin, A. (1993) J. Bone Miner. Res. 8:147-155; and Shankar, G. and Stern, P. H. (1993) Bone 14:871-876), hepatitis, including alcoholic hepatitis (see e.g., McClain, C. J. and Cohen, D. A. (1989) Hepatology 9:349-35 1; Felver, M. E., et al. (1990) Alcohol. Clin. Exp. Res. 14:255-259; and Hansen, J., et al. (1994) Hepatology 20:461-474) and viral hepatitis (Sheron, N., et al. (1991) J. Hepatol. 12:241-245; and Hussain, M. J., et al. (1994) J. Clin. Pathol. 47:1112-1115), coagulation disturbances (see e.g., van der Poll, T., et al. (1990) N. Engl. J. Med. 322:1622-1627; and van der Poll, T., et al. (1991) Prog. Clin. Biol. Res. 367:55-60), burns (see e.g., Giroir, B. P., et al. (1994) Am. J. Physiol. 267:H1 18-124; and Liu, X. S., et al. (1994) Burns 20:40-44), reperfusion injury (see e.g., Scales, W. E., et al. (1994) Am. J. Physiol. 267:G1122-1127; Serrick, C., et al. (1994) Transplantation 58:1158-1162; and Yao, Y. M., et al. (1995) Resuscitation 29:157-168), keloid formation (see e.g., McCauley, R. L., et al. (1992) J. Clin. Immunol. 12:300-308), scar tissue formation; pyrexia; periodontal disease; obesity and radiation toxicity.
  • Other disorders in which TNFα activity is detrimental include, but are not limited to, adult Still's disease, Alzheimer's disease, ankylosing spondylitis, asthma, cancer and cachexia, atherosclerosis, chronic atherosclerosis, chronic fatigue syndrome, liver failure, chronic liver failure, obstructive pulmonary disease, chronic obstructive pulmonary disease, congestive heart failure, dermatopolymyositis, diabetic macrovasculopathy, endometriosis, familial periodic fevers, fibrosis, hemodialysis, Jarisch-Herxheimer reaction, juvenile RA, Kawasaki syndrome, myelo dysplastic syndrome, myocardial infarction, panciaticular vulgaris, periodontal disease, peripheral neuropathy, polyarticular, polymyositis, progressive renal failure, psoriasis, psoriatic arthritis, Reiter's syndrome, sarcoidosis, scleroderma, spondyloarthropathies, Still's disease, stroke, therapy associated syndrome, therapy induced inflammatory syndrome, inflammatory syndrome following IL-2 administration, thoracoabdominal aortic aneurysm repair (TAAA), Vasulo-Behcet's disease, Yellow Fever vaccination, type 1 diabetes mellitus, type 2 diabetes mellitus, neuropathic pain, sciatica, cerebral edema, edema in and/or around the spinal cord, vasculitide, Wegener's granulomatosis, temporal arteritis, polymyalgia rheumatica, Takayasu's arteritis, polyarteritis nodosa, microscopic polyangiitis, Churg-Strauss syndrome, Felty's syndrome, Sjogren's syndrome, mixed connective tissue disorder, relapsing polychondritis, pseudogout, loosening of prostheses, autoimmune hepatitis, sclerosing cholangitis, acute pancreatitis, chronic pancreatitis, glomerulonephritides, post-streptococcal glomerulonephritis or IgA nephropathy, rheumatic heart disease, cardiomyopathy, orchitis, pyoderma gangerenosum, multiple myeloma, TNF receptor associated periodic syndrome [TRAPS], atherosclerosis, steroid dependent giant cell arteritismyostitis, uveitis, and drug reactions. [0112]
  • The invention is further illustrated in the following examples, which should not be construed as further limiting. The contents of all references, pending patent applications and published patents, cited throughout this application are hereby expressly incorporated by reference.[0113]
    • EXAMPLES Example 1 Preparation of the Formulation
  • The pharmaceutical formulation of the invention was made according to the following protocol. [0114]
  • Materials which were used in the formulation include: mannitol, citric acid monohydrate (citric acid), sodium citrate, disodium phosphate dihydrate (dibasic sodium phosphate dihydrate), sodium dihydrogen phosphate dihydrate (monobasic sodium phosphate dihydrate), sodium chloride, polysorbate 80, water for the injections, sodium hydroxide, which was used as a 1M solution to adjust the pH, and protein concentrate (e.g., antibody concentrate). [0115]
  • Preparation of 20L of Buffer (Equivalent to 20.180 kg—Density of the Solution: 1.009 g/ml [0116]
  • Ingredients were weighed out as follows: 240.0 g mannitol, 26.1 g citric acid monohydrate, 6.1 g sodium citrate, 30.6 g disodium phosphate dihydrate, 17.2 g sodium dihydrogen phosphate dihydrate, 123.3 g sodium chloride, 20.0 g polysorbate 80, and 19,715.7 to 19,716.1 g of water. [0117]
  • A sodium hydroxide solution was prepared by combining 40.0 g of sodium hydroxide with 1000.8 g of water for injections. [0118]
  • Next, a buffer was prepared by dissolving the following pre-weighed ingredients (described above) in about 90% of the water for injections: mannitol, citric acid monohydrate, sodium citrate, disodium phosphate dihydrate, sodium dihydrogen phosphate, sodium chloride, and polysorbate 80. It was determined that the sequence of the addition of the buffer constituents was not important and can, therefore, be chosen at will. [0119]
  • Following addition of all of the buffer constituents, the pH of the solution was adjusted with 1M sodium hydroxide which was prepared as described above. After the addition of the sodium hydroxide, the final weight of the water was added. The buffer solution was then filtered through a sterilized filter (hydrophilic polyvinylidene difluoride, 0.22 μm pore size) into a sterilized receptacle. The filtration medium used was filtration sterilized nitrogen. [0120]
  • Preparation of 40L of Formulation (Equivalent to 40.88 kg) [0121]
  • The filtered buffer solution was then added to the thawed and pooled antibody concentrate (the active ingredient of the pharmaceutical formulation), prepared as follows. The antibody (concentrate) was thawed in a water bath prior to the preparation of the pharmaceutical formulation. 34.207 g of antibody concentrate was used, which is equivalent to 2.0 kg of protein with 60 mg protein/mL protein concentrate. The density of the concentrate was 1.0262 g/mL. Any protein concentrate ranging from 25.655 to 37.316, which is equivalent to a protein concentration in the protein concentrate of 55 to 80 mg/mL, can be used. The buffer was added while stirring, until the final weight of the bulk solution was reached. [0122]
  • The formulation, with all of its ingredients included, was then sterilized by filtration as described above, except the formulation was filtered through two sterile 0.22 μm membrane filters. Following sterilization, the formulation was packaged for use in either a vial or a pre-filled syringe. [0123]
  • The skilled artisan will also appreciate that the weight quantities and/or weight-to-volume ratios recited herein, can be converted to moles and/or molarities using the art-recognized molecular weights of the recited ingredients. Weight quantities exemplified herein (e.g., g or kg) are for the volumes (e.g., of buffer or pharmaceutical formulation) recited. The skilled artisan will appreciate that the weight quantities can be proportionally adjusted when different formulation volumes are desired. For example, 32L, 20L, 10L, 5L, or 1L formulations would include 80%, 50%, 25%, 12.5%, or 2.5%, respectively, of the exemplified weight quantities. [0124]
    • Example 2 Freeze/Thaw Studies
  • After the formulation buffer for the D2E7 antibody was selected the drug substance was formulated in the same matrix as the finished product. [0125]
  • Freeze thaw behavior of the D2E7 antibody drug substance at a protein concentration of 63 mg/mL was evaluated by cycling drug substance 3 times from the frozen state to the liquid state. Table N shows the results of an experiment evaluating the effect of three fast and slow freeze-thaw cycles in the presence and absence of 0.1% polysorbate 80 starting from −80° C. or −30° C., respectively. [0126]
  • Table 2 shows that the D2E7 antibody drug substance can be thawed/frozen at least 3 times without any detrimental effect on either chemical (cation exchange HPLC, size exclusion HPLC, colour, pH), physicochemical properties (subvisible particles, clarity) or biological activity (in vitro TNF neutralization assay). Also table 2 shows that the inclusion of polysorbate 80 improved the physicochemical properties of the D2E7 antibody drug substance as evidenced by the lower number of subvisible particles regardless whether a slow or fast freeze/thaw cycle was being used (see shaded areas in table 2). [0127]
    TABLE 2
    Effect of freeze thaw on the D2E7 antibody drug substance
    with/without polysorbate 80
    Fast
    Fast thaw thaw
    Poly- No Slow thaw −30° C. in Slow thaw −80° C. in
    sorbate freeze/ −30° C. in water −80° in water
    Test criteria (0.1%)1) thaw refrigerator bath refrigerator bath
    Clarity − 25.0 22.5 25.3 25.8 25.6
    + 27.8 28.1 28.2 28.0 28.1
    Colour − ≦B9 ≦B9 ≦B9 ≦B9 ≦B9
    + ≦B9 ≦B9 ≦B9 ≦B9 ≦B9
    pH − 5.01 5.02 5.02 5.02 5.02
    + 5.02 5.02 5.02 5.02 5.02
    Subvisible − 42 600 303 1891 303
    particles 2 4 5 8 0
    + 0 5 1 0 8
    0 0 0 0 1
    Size − 99.8 99.8 99.8 99.8 99.8
    exclusion
    HPLC + 99.8 99.8 99.8 99.8 99.8
    Cation − 87.1 87.0 87.2 86.9 86.9
    exchange + 86.8 87.0 87.1 87.3 86.8
    HPLC
    In vitro TNF − 118.0 123.8 118.0 103.3 120.5
    neutrali- + 111.8 96.2 100.9 96.7 95.8
    zation test
    • Example 3 Microbial Studies
  • Tests were performed to determine if the formulation can support microbial growth. The results from these experiments showed that the formulation does not support microbial growth if stored at 20 to 25° C. for 14 days. This result was determined by directly inoculating the sterile formulation with microorganisms (e.g., [0128] Staphylococous aureus, ATCC-No.: 6538P, Candida albicans, ATCC-No.: 10231, Aspergillus niger, ATCCC-No.: 16404, Pseudomonas aeruginosa, ATCC-No.: 9027, an environmental isolate) at low level (NMT 100 cfu/mL). Inoculated formulations were then examined for overall microbial growth, e.g., for changes in turbidity. A lack of turbidity was an indication of no overall growth, and was detected in the inoculated containers after 14 days. Further, no organisms could be reisolated from these containers. Thus it was concluded that the formulation does not support microbial growth under these conditions.
  • Incorporation by Reference [0129]
  • The contents of all references and patents cited herein are hereby incorporated by reference in their entirety. [0130]
  • Equivalents [0131]
  • Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims. [0132]
  • 0
    SEQUENCE LISTING
    <160> NUMBER OF SEQ ID NOS: 34
    <210> SEQ ID NO 1
    <211> LENGTH: 108
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 1
    Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
    1 5 10 15
    Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn
    20 25 30
    Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
    35 40 45
    Ile Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser
    50 55 60
    Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
    65 70 75 80
    Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro
    85 90 95
    Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
    100 105
    <210> SEQ ID NO 2
    <211> LENGTH: 122
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 2
    Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
    1 5 10 15
    Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp
    20 25 30
    Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
    35 40 45
    Val Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser
    50 55 60
    Val Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu
    65 70 75 80
    Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
    85 90 95
    Cys Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp
    100 105 110
    Gly Gln Gly Thr Leu Val Thr Val Ser Ser
    115 120
    <210> SEQ ID NO 3
    <211> LENGTH: 10
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <220> FEATURE:
    <221> NAME/KEY: VARIANT
    <222> LOCATION: 10
    <223> OTHER INFORMATION: Xaa = Thr or Ala
    <400> SEQUENCE: 3
    Pro Gln Arg Tyr Asn Arg Ala Pro Tyr Xaa
    1 5 10
    <210> SEQ ID NO 4
    <211> LENGTH: 13
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <220> FEATURE:
    <221> NAME/KEY: VARIANT
    <222> LOCATION: 13
    <223> OTHER INFORMATION: Xaa = Tyr or Asn
    <400> SEQUENCE: 4
    Pro Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Xaa
    1 5 10
    <210> SEQ ID NO 5
    <211> LENGTH: 8
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 5
    Pro Ala Ala Ser Thr Leu Gln Ser
    1 5
    <210> SEQ ID NO 6
    <211> LENGTH: 18
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 6
    Pro Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val
    1 5 10 15
    Glu Gly
    <210> SEQ ID NO 7
    <211> LENGTH: 12
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 7
    Pro Arg Ala Ser Gln Gly Ile Arg Asn Tyr Leu Ala
    1 5 10
    <210> SEQ ID NO 8
    <211> LENGTH: 6
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 8
    Pro Asp Tyr Ala Met His
    1 5
    <210> SEQ ID NO 9
    <400> SEQUENCE: 9
    000
    <210> SEQ ID NO 10
    <400> SEQUENCE: 10
    000
    <210> SEQ ID NO 11
    <211> LENGTH: 10
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 11
    Pro Gln Lys Tyr Asn Ser Ala Pro Tyr Ala
    1 5 10
    <210> SEQ ID NO 12
    <211> LENGTH: 10
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 12
    Pro Gln Lys Tyr Asn Arg Ala Pro Tyr Ala
    1 5 10
    <210> SEQ ID NO 13
    <211> LENGTH: 10
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 13
    Pro Gln Lys Tyr Gln Arg Ala Pro Tyr Thr
    1 5 10
    <210> SEQ ID NO 14
    <211> LENGTH: 10
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 14
    Pro Gln Lys Tyr Ser Ser Ala Pro Tyr Thr
    1 5 10
    <210> SEQ ID NO 15
    <211> LENGTH: 10
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 15
    Pro Gln Lys Tyr Asn Ser Ala Pro Tyr Thr
    1 5 10
    <210> SEQ ID NO 16
    <211> LENGTH: 10
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 16
    Pro Gln Lys Tyr Asn Arg Ala Pro Tyr Thr
    1 5 10
    <210> SEQ ID NO 17
    <211> LENGTH: 10
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 17
    Pro Gln Lys Tyr Asn Ser Ala Pro Tyr Tyr
    1 5 10
    <210> SEQ ID NO 18
    <211> LENGTH: 10
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 18
    Pro Gln Lys Tyr Asn Ser Ala Pro Tyr Asn
    1 5 10
    <210> SEQ ID NO 19
    <211> LENGTH: 10
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 19
    Pro Gln Lys Tyr Thr Ser Ala Pro Tyr Thr
    1 5 10
    <210> SEQ ID NO 20
    <211> LENGTH: 10
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 20
    Pro Gln Lys Tyr Asn Arg Ala Pro Tyr Asn
    1 5 10
    <210> SEQ ID NO 21
    <211> LENGTH: 10
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 21
    Pro Gln Lys Tyr Asn Ser Ala Ala Tyr Ser
    1 5 10
    <210> SEQ ID NO 22
    <211> LENGTH: 10
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 22
    Pro Gln Gln Tyr Asn Ser Ala Pro Asp Thr
    1 5 10
    <210> SEQ ID NO 23
    <211> LENGTH: 10
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 23
    Pro Gln Lys Tyr Asn Ser Asp Pro Tyr Thr
    1 5 10
    <210> SEQ ID NO 24
    <211> LENGTH: 10
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 24
    Pro Gln Lys Tyr Ile Ser Ala Pro Tyr Thr
    1 5 10
    <210> SEQ ID NO 25
    <211> LENGTH: 10
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 25
    Pro Gln Lys Tyr Asn Arg Pro Pro Tyr Thr
    1 5 10
    <210> SEQ ID NO 26
    <211> LENGTH: 10
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 26
    Pro Gln Arg Tyr Asn Arg Ala Pro Tyr Ala
    1 5 10
    <210> SEQ ID NO 27
    <211> LENGTH: 13
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 27
    Pro Ala Ser Tyr Leu Ser Thr Ser Ser Ser Leu Asp Asn
    1 5 10
    <210> SEQ ID NO 28
    <211> LENGTH: 13
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 28
    Pro Ala Ser Tyr Leu Ser Thr Ser Ser Ser Leu Asp Lys
    1 5 10
    <210> SEQ ID NO 29
    <211> LENGTH: 13
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 29
    Pro Ala Ser Tyr Leu Ser Thr Ser Ser Ser Leu Asp Tyr
    1 5 10
    <210> SEQ ID NO 30
    <211> LENGTH: 13
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 30
    Pro Ala Ser Tyr Leu Ser Thr Ser Ser Ser Leu Asp Asp
    1 5 10
    <210> SEQ ID NO 31
    <211> LENGTH: 13
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 31
    Pro Ala Ser Tyr Leu Ser Thr Ser Phe Ser Leu Asp Tyr
    1 5 10
    <210> SEQ ID NO 32
    <211> LENGTH: 13
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 32
    Pro Ala Ser Tyr Leu Ser Thr Ser Ser Ser Leu His Tyr
    1 5 10
    <210> SEQ ID NO 33
    <211> LENGTH: 13
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 33
    Pro Ala Ser Phe Leu Ser Thr Ser Ser Ser Leu Glu Tyr
    1 5 10
    <210> SEQ ID NO 34
    <211> LENGTH: 13
    <212> TYPE: PRT
    <213> ORGANISM: Artificial Sequence
    <220> FEATURE:
    <223> OTHER INFORMATION: mutated human antibody
    <400> SEQUENCE: 34
    Pro Ala Ser Tyr Leu Ser Thr Ala Ser Ser Leu Glu Tyr
    1 5 10

Claims (23)

What is claimed is:
1. A pharmaceutical formulation selected frrom the group consisting of:
(a) A liquid aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody in a buffered solution, said formulation having a pH between about 4 and 8 and having a shelf life of at least 18 months.
(b) An aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody in a buffered solution, said formulation having a pH between about 4 and 8 and having a shelf life of at least 18 months in the liquid state.
(c) A liquid aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody in a buffered solution, said formulation having a pH between about 4 and 8 which maintains stability following at least 3 freeze/thaw cycles of the formulation.
(d) A liquid aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody in a buffered solution, said formulation having a pH between 4 and 8 and having enhanced stability of at least 12 months at a temperature of 2-8° C.
2. The formulation of claim 1, wherein the antibody is directed to TNFα.
3. The formulation of claim 1, wherein the concentration of the antibody is between about 1-150 mg/ml.
4. The formulation of claim 1, wherein the concentration of the antibody is about 50 mg/ml.
5. The formulation of claim 1, which further is suitable for single use sc injection.
6. The formulation of claim 1, wherein the antibody is an antibody, or an antigen-binding portion thereof, that dissociates from human TNFα with a Kd of 1×10−8 M or less and a Koff rate constant of 1×10−3 s−1 or less, both determined by surface plasmon resonance, and neutralizes human TNFα cytotoxicity in a standard in vitro L929 assay with an IC50 of 1×10−7 M or less.
7. The formulation of claim 6, wherein the antibody, or antigen-binding portion thereof, is a recombinant antibody, or antigen-binding portion thereof.
8. The formulation of claim 1, wherein the antibody is an the antibody, or antigen-binding portion, thereof which:
a) dissociates from human TNFα with a Koff rate constant of 1×10−3 s−1 or less, as determined by surface plasmon resonance;
b) has a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9;
c) has a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12.
9. The formulation of claim 1, wherein the antibody, or antigen-binding portion thereof, has a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2.
10. The formulation of claim 1, wherein the antibody, or antigen-binding portion thereof, neutralizes the activity of human TNFα, chimpanzee TNFα and at least one additional primate TNFα selected from the group consisting of baboon TNFα, marmoset TNFα, cynomolgus TNFα and rhesus TNFα.
11. The formulation of claim 1, wherein the antibody, or an antigen-binding portion thereof, also neutralizes the activity of mouse TNFα and/or pig TNFα.
12. The formulation of claim 1, wherein the antibody, or antigen-binding portion thereof, binds human TNFα and is the antibody D2E7 or an antigen binding portion thereof.
13. An aqueous pharmaceutical composition comprising a polyol, a surfactant, and a buffer system comprising citrate and/or phosphate with a pH of about 4 to 8, in amounts sufficient to formulate an antibody for therapeutic use at a concentration of greater than about 45 mg/ml.
14. The composition of claim 13, wherein the polyol is mannitol and the surfactant is polysorbate 80.
15. The composition of claim 14, which contains 5-20 mg/ml of mannitol and 0.1-10 mg/ml of polysorbate 80.
16. The formulation of claim 13, which contains an antibody, or antigen-binding portion thereof, which binds human TNFα and is the antibody D2E7 or an antigen binding portion thereof.
17. A liquid aqueous pharmaceutical formulation comprising
(a) 1-150 mg/ml of antibody,
(b) 5-20 mg/ml of mannitol,
(c) 0.1-10 mg/ml of Tween-80, and
(d) a buffer system comprising citrate and/or phosphate, with a pH of 4 to 8.
18. The formulation of claim 17, wherein the pH is selected from the group consisting of between about 4.5 to about 6.0, between about 4.8 to about 5.5, and between about 5.0 to about 5.2.
19. The liquid aqueous pharmaceutical formulation of claim 17, which contains
(a) about 50 mg/ml of antibody,
(b) about 12 mg/ml of mannitol,
(c) about 1 mg/ml of Tween-80, and
20. The formulation of claim 17, wherein the buffer system comprises
(a) about 1.3 mg/ml of citric acid,
(b) about 0.3 mg/ml of sodium citrate,
(c) about 1.5 mg/ml of disodium phosphate dihydrate,
(d) about 0.9 mg/ml of sodium dihydrogen phosphate dihydrate, and
(e) about 6.2 mg/ml of sodium chloride
21. The formulation of claim 19, wherein the antibody is directed to TNFα.
22. The formulation of claim 19, wherein the antibody, or antigen-binding portion thereof, binds human TNFα and is the antibody D2E7 or an antigen binding portion thereof.
23. The formulation of claim 22, which is administered to a subject suffering from a disorder in which TNFα activity is detrimental such that TNFα activity in the subject is inhibited
US10/222,140 2002-08-16 2002-08-16 Formulation of human antibodies for treating TNF-alpha associated disorders Abandoned US20040033228A1 (en)

Priority Applications (86)

Application Number Priority Date Filing Date Title
US10/222,140 US20040033228A1 (en) 2002-08-16 2002-08-16 Formulation of human antibodies for treating TNF-alpha associated disorders
MYPI20070749A MY162068A (en) 2002-08-16 2003-08-08 Formulation of human antibodies for treating tnf-(alpha) associated disorders
MYPI20033010A MY153718A (en) 2002-08-16 2003-08-08 Formulation of human antibodies for treating tnf-(?) associated disorders
MYPI2012001176A MY163027A (en) 2002-08-16 2003-08-08 FORMULATION OF HUMAN ANTIBODIES FOR TREATING TNF-(α) ASSOCIATED DISORDERS
TW092122123A TWI331532B (en) 2002-08-16 2003-08-12 Formulation of human antibodies for treating tnf-alpha associated disorders
ES10182610.5T ES2636692T3 (en) 2002-08-16 2003-08-15 Formulation of human antibodies to treat disorders associated with TNF-alpha
EP10182610.5A EP2359856B1 (en) 2002-08-16 2003-08-15 Formulation of human antibodies for treating TNF-alpha associated disorders
EP10182625A EP2363145A1 (en) 2002-08-16 2003-08-15 Pharmaceutical anti-TNF-alpha antibody formulation
US10/525,292 US8216583B2 (en) 2002-08-16 2003-08-15 Formulation of human antibodies for treating TNF-α associated disorders
PT03748439T PT1528933E (en) 2002-08-16 2003-08-15 Pharmaceutical anti-tnf-alpha antibody formulation
AU2003267744A AU2003267744C1 (en) 2002-08-16 2003-08-15 Pharmaceutical anti-TNF-alpha antibody formulation
KR1020117007142A KR101273568B1 (en) 2002-08-16 2003-08-15 Pharmaceutical anti-TNF-α antibody formulation
CA2882905A CA2882905C (en) 2002-08-16 2003-08-15 Anti-tnf-alpha antibodies in solution and uses thereof
MXPA05001841A MXPA05001841A (en) 2002-08-16 2003-08-15 Pharmaceutical anti-tnf-alpha antibody formulation.
AT03748439T ATE555809T1 (en) 2002-08-16 2003-08-15 PHARMACEUTICAL ANTI-TNF-ALPHA ANTIBODIES FORMULATION
CA2872088A CA2872088A1 (en) 2002-08-16 2003-08-15 Anti-tnf-alpha antibodies in solution and uses thereof
CN201010613919.XA CN102078608B (en) 2002-08-16 2003-08-15 Be used for the treatment of the preparation of people's antibody of TNF-α associated conditions
CN201010613946.7A CN102049045B (en) 2002-08-16 2003-08-15 Be used for the treatment of the preparation of people's antibody of TNF-α associated conditions
UY27940A UY27940A1 (en) 2002-08-16 2003-08-15 FORMULATION OF HUMAN ANTIBODIES FOR THE TREATMENT OF DISORDERS ASSOCIATED WITH TNF-A
EP03748439A EP1528933B1 (en) 2002-08-16 2003-08-15 Pharmaceutical anti-tnf-alpha antibody formulation
BR0313492-0A BR0313492A (en) 2002-08-16 2003-08-15 Human antibody formulation to treat tnf-alpha associated disorders
PL398596A PL218221B1 (en) 2002-08-16 2003-08-15 Preparation containing human antibodies for the treatment of disorders associated with TNF-α
NZ538030A NZ538030A (en) 2002-08-16 2003-08-15 Formulation of human antibodies for treating TNF-alpha associated disorders
KR1020137022247A KR101529583B1 (en) 2002-08-16 2003-08-15 Pharmaceutical anti-TNF-α antibody formulation
PCT/IB2003/004502 WO2004016286A2 (en) 2002-08-16 2003-08-15 Pharmaceutical anti-tnf-alpha antibody formulation
AR20030102982A AR040881A1 (en) 2002-08-16 2003-08-15 FORMULATION OF HUMAN ANTIBODIES FOR THE TREATMENT OF DISORDERS ASSOCIATED WITH TNF-ALFA
CA2494756A CA2494756C (en) 2002-08-16 2003-08-15 Anti-tnf-alpha antibodies in solution and uses thereof
CA2872091A CA2872091A1 (en) 2002-08-16 2003-08-15 Anti-tnf-alpha antibodies in solution and uses thereof
EP10182598A EP2363144A1 (en) 2002-08-16 2003-08-15 Pharmaceutical anti-TNF-alpha antibody formulation
EP20100182619 EP2361637A1 (en) 2002-08-16 2003-08-15 Formulation of human antibodies for treating TNF-alpha associated disorders
SI200332176T SI1528933T1 (en) 2002-08-16 2003-08-15 Pharmaceutical anti-tnf-alpha antibody formulation
PT101826105T PT2359856T (en) 2002-08-16 2003-08-15 Formulation of human antibodies for treating tnf-alpha associated disorders
KR1020127026957A KR101367743B1 (en) 2002-08-16 2003-08-15 Pharmaceutical anti-TNF-α antibody formulation
PE2003000831A PE20040994A1 (en) 2002-08-16 2003-08-15 FORMULATION OF HUMAN ANTIBODIES REFERRED TO DISORDERS ASSOCIATED WITH TNF-ALPHA
CN200910253163.XA CN101721702B (en) 2002-08-16 2003-08-15 Formulation of human antibodies for treating TNF-alpha associated disorders
DK03748439.1T DK1528933T3 (en) 2002-08-16 2003-08-15 Pharmaceutical anti-TNF-alpha antibody formulation
CA2854798A CA2854798A1 (en) 2002-08-16 2003-08-15 Anti-tnf-alpha antibodies in solution and uses thereof
CA2882931A CA2882931C (en) 2002-08-16 2003-08-15 Anti-tnf-alpha antibodies in solution and uses thereof
CN038242729A CN1688339B (en) 2002-08-16 2003-08-15 Formulation of human antibodies for treating TNF-alpha associated disorders
JP2004528780A JP4925582B2 (en) 2002-08-16 2003-08-15 Formulation of human antibody for treatment of TNF-alpha related diseases
ES03748439T ES2387616T3 (en) 2002-08-16 2003-08-15 Pharmaceutical formulation of anti-TNF-alpha antibodies
KR1020057002604A KR20050067140A (en) 2002-08-16 2003-08-15 Pharmaceutical anti-TNF-αantibody formulation
SI200332534T SI2359856T1 (en) 2002-08-16 2003-08-15 Formulation of human antibodies for treating TNF-alpha associated disorders
CA2882934A CA2882934C (en) 2002-08-16 2003-08-15 Anti-tnf-alpha antibodies in solution and uses thereof
PL375272A PL212934B1 (en) 2002-08-16 2003-08-15 Pharmaceutical anti-tnf-alpha antibody formulation
PL406852A PL218834B1 (en) 2002-08-16 2003-08-15 Formulation containing human antibodies for the treatment of disorders associated with TNF-α
CA2882907A CA2882907C (en) 2002-08-16 2003-08-15 Anti-tnf-alpha antibodies in solution and uses thereof
DK10182610.5T DK2359856T3 (en) 2002-08-16 2003-08-15 Formulation of human antibodies for treating TNF-alpha associated disorders
CA2872089A CA2872089C (en) 2002-08-16 2003-08-15 Anti-tnf-alpha antibodies in solution and uses thereof
ZA200501032A ZA200501032B (en) 2002-08-16 2005-02-03 Pharmaceutical anti-TNF-alpha antibody formulation.
IL166809A IL166809A (en) 2002-08-16 2005-02-10 Liquid aqueous formulations comprising human anti-tnf alpha antibodies
HK05108068.5A HK1074008A1 (en) 2002-08-16 2005-09-15 Pharmaceutical anti-tnf-alpha antibody formulation
CL2010000603A CL2010000603A1 (en) 2002-08-16 2010-06-08 A liquid aqueous pharmaceutical formulation comprising an antibody against human htnf-alpha or an antigen binding portion thereof, a polyol; a surfactant; a buffer system of ph (div. sol. 1643-03).
ARP100102557A AR077412A2 (en) 2002-08-16 2010-07-14 PHARMACEUTICAL FORMULATION PHARMACEUTICAL COMPOSICON ACUOSA AND PHARMACEUTICAL FORMULATION ACUOSA LIQUIDA INCLUDING AN ANTIBODY
IL207028A IL207028A (en) 2002-08-16 2010-07-15 Pharmaceutical anti-tnf-alpha antibody formulation
JP2011204759A JP5608619B2 (en) 2002-08-16 2011-09-20 Formulation of human antibodies for the treatment of TNF-alpha related diseases
US13/471,820 US8932591B2 (en) 2002-08-16 2012-05-15 Formulation of human antibodies for treating TNF-α associated disorders
CY20121100631T CY1113353T1 (en) 2002-08-16 2012-07-17 PHARMACEUTICAL FORM ANTI-TNF-ALPHA
JP2013235924A JP2014074034A (en) 2002-08-16 2013-11-14 Formulation of human antibodies for treating tnf-alpha associated disorders
US14/091,938 US8795670B2 (en) 2002-08-16 2013-11-27 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/091,661 US8802100B2 (en) 2002-08-16 2013-11-27 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/091,888 US8802101B2 (en) 2002-08-16 2013-11-27 Formulation of human antibodies for treating TNF-α associated disorders
US14/147,287 US8802102B2 (en) 2002-08-16 2014-01-03 Formulation of human antibodies for treating TNF-α associated disorders
US14/322,581 US8911741B2 (en) 2002-08-16 2014-07-02 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/322,565 US8940305B2 (en) 2002-08-16 2014-07-02 Formulation of human antibodies for treating TNF-α associated disorders
US14/453,490 US8916158B2 (en) 2002-08-16 2014-08-06 Formulation of human antibodies for treating TNF-α associated disorders
US14/453,461 US8916157B2 (en) 2002-08-16 2014-08-06 Formulation of human antibodies for treating TNF-α associated disorders
US14/558,182 US9114166B2 (en) 2002-08-16 2014-12-02 Formulation of human antibodies for treating TNF-α associated disorders
JP2015099796A JP2015199741A (en) 2002-08-16 2015-05-15 Formulation of human antibodies for treating tnf-alfa related disorders
US14/799,211 US9220781B2 (en) 2002-08-16 2015-07-14 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/826,357 US9327032B2 (en) 2002-08-16 2015-08-14 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/826,367 US9272041B2 (en) 2002-08-16 2015-08-14 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/826,377 US9295725B2 (en) 2002-08-16 2015-08-14 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/826,393 US9289497B2 (en) 2002-08-16 2015-08-14 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/826,383 US9272042B2 (en) 2002-08-16 2015-08-14 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/884,279 US9302011B2 (en) 2002-08-16 2015-10-15 Formulation of human antibodies for treating TNF-α associated disorders
US15/095,393 US9950066B2 (en) 2002-08-16 2016-04-11 Formulation of human antibodies for treating TNF-alpha associated disorders
US15/418,460 US9750808B2 (en) 2002-08-16 2017-01-27 Formulation of human antibodies for treating TNF-alpha associated disorders
US15/418,465 US9732152B2 (en) 2002-08-16 2017-01-27 Formulation of human antibodies for treating TNF-alpha associated disorders
US15/418,469 US9738714B2 (en) 2002-08-16 2017-01-27 Formulation of human antibodies for treating TNF-alpha associated disorders
JP2017074982A JP2017165736A (en) 2002-08-16 2017-04-05 Formulations of human antibodies for treating tnf-alpha associated disorders
CY20171100527T CY1118991T1 (en) 2002-08-16 2017-05-19 PHARMACEUTICAL FORM OF HUMAN ANTIBODIES FOR TREATMENT OF TNF-ALPHA DISORDERS
US15/918,663 US20190054171A1 (en) 2002-08-16 2018-03-12 Formulation of human antibodies for treating tnf-alpha associated disorders
US16/057,217 US20180339046A1 (en) 2002-08-16 2018-08-07 Formulation of human antibodies for treating tnf-alpha associated disorders
US17/126,500 US20210113694A1 (en) 2002-08-16 2020-12-18 Formulation of human antibodies for treating tnf-alpha associated disorders
US17/472,004 US20220241415A1 (en) 2002-08-16 2021-09-10 Formulation of human antibodies for treating tnf-alpha associated disorders

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US10/222,140 US20040033228A1 (en) 2002-08-16 2002-08-16 Formulation of human antibodies for treating TNF-alpha associated disorders

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US10/525,292 Continuation US8216583B2 (en) 2002-08-16 2003-08-15 Formulation of human antibodies for treating TNF-α associated disorders
PCT/IB2003/004502 Continuation WO2004016286A2 (en) 2002-08-16 2003-08-15 Pharmaceutical anti-tnf-alpha antibody formulation

Publications (1)

Publication Number Publication Date
US20040033228A1 true US20040033228A1 (en) 2004-02-19

Family

ID=31714885

Family Applications (27)

Application Number Title Priority Date Filing Date
US10/222,140 Abandoned US20040033228A1 (en) 2002-08-16 2002-08-16 Formulation of human antibodies for treating TNF-alpha associated disorders
US10/525,292 Active 2026-10-08 US8216583B2 (en) 2002-08-16 2003-08-15 Formulation of human antibodies for treating TNF-α associated disorders
US13/471,820 Expired - Lifetime US8932591B2 (en) 2002-08-16 2012-05-15 Formulation of human antibodies for treating TNF-α associated disorders
US14/091,661 Expired - Lifetime US8802100B2 (en) 2002-08-16 2013-11-27 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/091,888 Expired - Lifetime US8802101B2 (en) 2002-08-16 2013-11-27 Formulation of human antibodies for treating TNF-α associated disorders
US14/091,938 Expired - Lifetime US8795670B2 (en) 2002-08-16 2013-11-27 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/147,287 Expired - Lifetime US8802102B2 (en) 2002-08-16 2014-01-03 Formulation of human antibodies for treating TNF-α associated disorders
US14/322,581 Expired - Lifetime US8911741B2 (en) 2002-08-16 2014-07-02 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/322,565 Expired - Lifetime US8940305B2 (en) 2002-08-16 2014-07-02 Formulation of human antibodies for treating TNF-α associated disorders
US14/453,490 Expired - Lifetime US8916158B2 (en) 2002-08-16 2014-08-06 Formulation of human antibodies for treating TNF-α associated disorders
US14/453,461 Expired - Lifetime US8916157B2 (en) 2002-08-16 2014-08-06 Formulation of human antibodies for treating TNF-α associated disorders
US14/558,182 Expired - Lifetime US9114166B2 (en) 2002-08-16 2014-12-02 Formulation of human antibodies for treating TNF-α associated disorders
US14/799,211 Expired - Lifetime US9220781B2 (en) 2002-08-16 2015-07-14 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/826,393 Expired - Lifetime US9289497B2 (en) 2002-08-16 2015-08-14 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/826,367 Expired - Fee Related US9272041B2 (en) 2002-08-16 2015-08-14 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/826,383 Expired - Fee Related US9272042B2 (en) 2002-08-16 2015-08-14 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/826,377 Expired - Lifetime US9295725B2 (en) 2002-08-16 2015-08-14 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/826,357 Expired - Lifetime US9327032B2 (en) 2002-08-16 2015-08-14 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/884,279 Expired - Lifetime US9302011B2 (en) 2002-08-16 2015-10-15 Formulation of human antibodies for treating TNF-α associated disorders
US15/095,393 Expired - Lifetime US9950066B2 (en) 2002-08-16 2016-04-11 Formulation of human antibodies for treating TNF-alpha associated disorders
US15/418,465 Expired - Lifetime US9732152B2 (en) 2002-08-16 2017-01-27 Formulation of human antibodies for treating TNF-alpha associated disorders
US15/418,460 Expired - Lifetime US9750808B2 (en) 2002-08-16 2017-01-27 Formulation of human antibodies for treating TNF-alpha associated disorders
US15/418,469 Expired - Lifetime US9738714B2 (en) 2002-08-16 2017-01-27 Formulation of human antibodies for treating TNF-alpha associated disorders
US15/918,663 Abandoned US20190054171A1 (en) 2002-08-16 2018-03-12 Formulation of human antibodies for treating tnf-alpha associated disorders
US16/057,217 Abandoned US20180339046A1 (en) 2002-08-16 2018-08-07 Formulation of human antibodies for treating tnf-alpha associated disorders
US17/126,500 Abandoned US20210113694A1 (en) 2002-08-16 2020-12-18 Formulation of human antibodies for treating tnf-alpha associated disorders
US17/472,004 Pending US20220241415A1 (en) 2002-08-16 2021-09-10 Formulation of human antibodies for treating tnf-alpha associated disorders

Family Applications After (26)

Application Number Title Priority Date Filing Date
US10/525,292 Active 2026-10-08 US8216583B2 (en) 2002-08-16 2003-08-15 Formulation of human antibodies for treating TNF-α associated disorders
US13/471,820 Expired - Lifetime US8932591B2 (en) 2002-08-16 2012-05-15 Formulation of human antibodies for treating TNF-α associated disorders
US14/091,661 Expired - Lifetime US8802100B2 (en) 2002-08-16 2013-11-27 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/091,888 Expired - Lifetime US8802101B2 (en) 2002-08-16 2013-11-27 Formulation of human antibodies for treating TNF-α associated disorders
US14/091,938 Expired - Lifetime US8795670B2 (en) 2002-08-16 2013-11-27 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/147,287 Expired - Lifetime US8802102B2 (en) 2002-08-16 2014-01-03 Formulation of human antibodies for treating TNF-α associated disorders
US14/322,581 Expired - Lifetime US8911741B2 (en) 2002-08-16 2014-07-02 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/322,565 Expired - Lifetime US8940305B2 (en) 2002-08-16 2014-07-02 Formulation of human antibodies for treating TNF-α associated disorders
US14/453,490 Expired - Lifetime US8916158B2 (en) 2002-08-16 2014-08-06 Formulation of human antibodies for treating TNF-α associated disorders
US14/453,461 Expired - Lifetime US8916157B2 (en) 2002-08-16 2014-08-06 Formulation of human antibodies for treating TNF-α associated disorders
US14/558,182 Expired - Lifetime US9114166B2 (en) 2002-08-16 2014-12-02 Formulation of human antibodies for treating TNF-α associated disorders
US14/799,211 Expired - Lifetime US9220781B2 (en) 2002-08-16 2015-07-14 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/826,393 Expired - Lifetime US9289497B2 (en) 2002-08-16 2015-08-14 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/826,367 Expired - Fee Related US9272041B2 (en) 2002-08-16 2015-08-14 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/826,383 Expired - Fee Related US9272042B2 (en) 2002-08-16 2015-08-14 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/826,377 Expired - Lifetime US9295725B2 (en) 2002-08-16 2015-08-14 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/826,357 Expired - Lifetime US9327032B2 (en) 2002-08-16 2015-08-14 Formulation of human antibodies for treating TNF-alpha associated disorders
US14/884,279 Expired - Lifetime US9302011B2 (en) 2002-08-16 2015-10-15 Formulation of human antibodies for treating TNF-α associated disorders
US15/095,393 Expired - Lifetime US9950066B2 (en) 2002-08-16 2016-04-11 Formulation of human antibodies for treating TNF-alpha associated disorders
US15/418,465 Expired - Lifetime US9732152B2 (en) 2002-08-16 2017-01-27 Formulation of human antibodies for treating TNF-alpha associated disorders
US15/418,460 Expired - Lifetime US9750808B2 (en) 2002-08-16 2017-01-27 Formulation of human antibodies for treating TNF-alpha associated disorders
US15/418,469 Expired - Lifetime US9738714B2 (en) 2002-08-16 2017-01-27 Formulation of human antibodies for treating TNF-alpha associated disorders
US15/918,663 Abandoned US20190054171A1 (en) 2002-08-16 2018-03-12 Formulation of human antibodies for treating tnf-alpha associated disorders
US16/057,217 Abandoned US20180339046A1 (en) 2002-08-16 2018-08-07 Formulation of human antibodies for treating tnf-alpha associated disorders
US17/126,500 Abandoned US20210113694A1 (en) 2002-08-16 2020-12-18 Formulation of human antibodies for treating tnf-alpha associated disorders
US17/472,004 Pending US20220241415A1 (en) 2002-08-16 2021-09-10 Formulation of human antibodies for treating tnf-alpha associated disorders

Country Status (27)

Country Link
US (27) US20040033228A1 (en)
EP (5) EP2363144A1 (en)
JP (5) JP4925582B2 (en)
KR (4) KR20050067140A (en)
CN (4) CN102049045B (en)
AR (2) AR040881A1 (en)
AT (1) ATE555809T1 (en)
AU (1) AU2003267744C1 (en)
BR (1) BR0313492A (en)
CA (9) CA2872089C (en)
CL (1) CL2010000603A1 (en)
CY (2) CY1113353T1 (en)
DK (2) DK2359856T3 (en)
ES (2) ES2636692T3 (en)
HK (1) HK1074008A1 (en)
IL (2) IL166809A (en)
MX (1) MXPA05001841A (en)
MY (3) MY153718A (en)
NZ (1) NZ538030A (en)
PE (1) PE20040994A1 (en)
PL (3) PL218221B1 (en)
PT (2) PT1528933E (en)
SI (2) SI2359856T1 (en)
TW (1) TWI331532B (en)
UY (1) UY27940A1 (en)
WO (1) WO2004016286A2 (en)
ZA (1) ZA200501032B (en)

Cited By (107)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030235585A1 (en) * 2001-06-08 2003-12-25 Fischkoff Steven A. Methods of administering anti-TNFalpha antibodies
US20040009172A1 (en) * 2002-04-26 2004-01-15 Steven Fischkoff Use of anti-TNFalpha antibodies and another drug
US20040126372A1 (en) * 2002-07-19 2004-07-01 Abbott Biotechnology Ltd. Treatment of TNFalpha related disorders
US20040166111A1 (en) * 2002-10-24 2004-08-26 Zehra Kaymakcalan Low dose methods for treating disorders in which TNFalpha activity is detrimental
WO2005063291A1 (en) * 2003-12-25 2005-07-14 Kirin Beer Kabushiki Kaisha Stable water-based medicinal preparation containing antibody
US20060009385A1 (en) * 2004-04-09 2006-01-12 Abbott Biotechnology Ltd. Multiple-variable dose regimen for treating TNFalpha-related disorders
US20060083741A1 (en) * 2004-10-08 2006-04-20 Hoffman Rebecca S Treatment of respiratory syncytial virus (RSV) infection
US20060153846A1 (en) * 2002-08-16 2006-07-13 Hans-Juergen Krause Formulation of human antibodies for treating tnf-alpha associated disorders
US20060269543A1 (en) * 2005-05-19 2006-11-30 Amgen Inc. Compositions and methods for increasing the stability of antibodies
US20070041905A1 (en) * 2005-08-19 2007-02-22 Hoffman Rebecca S Method of treating depression using a TNF-alpha antibody
US20070071747A1 (en) * 2005-05-16 2007-03-29 Hoffman Rebecca S Use of TNFalpha inhibitor for treatment of erosive polyarthritis
EP1798504A1 (en) * 2005-12-19 2007-06-20 Koninklijke Philips Electronics N.V. Method of making dried particles
US20070172897A1 (en) * 2005-11-01 2007-07-26 Maksymowych Walter P Methods and compositions for diagnosing ankylosing spondylitis using biomarkers
US20070249813A1 (en) * 1996-02-09 2007-10-25 Salfeld Jochen G Human antibodies that bind human TNFa
US20070292442A1 (en) * 2006-04-05 2007-12-20 Min Wan Antibody purification
US20080112953A1 (en) * 2006-10-06 2008-05-15 Amgen Inc. Stable formulations
US20080118496A1 (en) * 2006-04-10 2008-05-22 Medich John R Uses and compositions for treatment of juvenile rheumatoid arthritis
US20080124326A1 (en) * 2006-10-20 2008-05-29 Amgen Inc. Stable polypeptide formulations
WO2008063213A2 (en) 2006-04-10 2008-05-29 Abbott Biotechnology Ltd. Uses and compositions for treatment of psoriatic arthritis
US20080131374A1 (en) * 2006-04-19 2008-06-05 Medich John R Uses and compositions for treatment of rheumatoid arthritis
US20080166348A1 (en) * 2006-04-10 2008-07-10 Hartmut Kupper Uses and compositions for treatment of rheumatoid arthritis
WO2008154543A2 (en) 2007-06-11 2008-12-18 Abbott Biotechnology Ltd. Methods for treating juvenile idiopathic arthritis
US20080311043A1 (en) * 2006-06-08 2008-12-18 Hoffman Rebecca S Uses and compositions for treatment of psoriatic arthritis
US20090017472A1 (en) * 2007-05-31 2009-01-15 Bruno Stuhlmuller BIOMARKERS PREDICTIVE OF THE RESPONSIVENESS TO TNFalpha INHIBITORS IN AUTOIMMUNE DISORDERS
US20090110679A1 (en) * 2007-07-13 2009-04-30 Luk-Chiu Li Methods and compositions for pulmonary administration of a TNFa inhibitor
US20090214535A1 (en) * 2005-06-10 2009-08-27 Chugai Seiyaku Kabushiki Kaisha Pharmaceutical Compositions Containing sc(Fv)2
US7588761B2 (en) 1996-02-09 2009-09-15 Abbott Biotechnology Ltd. Human antibodies that bind human TNFα
US20090271164A1 (en) * 2008-01-03 2009-10-29 Peng Joanna Z Predicting long-term efficacy of a compound in the treatment of psoriasis
US20090280065A1 (en) * 2006-04-10 2009-11-12 Willian Mary K Uses and Compositions for Treatment of Psoriasis
US20090317399A1 (en) * 2006-04-10 2009-12-24 Pollack Paul F Uses and compositions for treatment of CROHN'S disease
US20100021451A1 (en) * 2006-06-08 2010-01-28 Wong Robert L Uses and compositions for treatment of ankylosing spondylitis
US20100034823A1 (en) * 2006-10-27 2010-02-11 Borhani David W Crystalline anti-hTNFalpha antibodies
US20100160894A1 (en) * 2006-06-30 2010-06-24 Julian Joseph F Automatic injection device
EP2231175A2 (en) 2007-11-30 2010-09-29 Abbott Laboratories Protein formulations and methods of making same
US20100266613A1 (en) * 2009-04-16 2010-10-21 Harding Fiona A Anti-tnf-alpha antibodies and their uses
US20100278822A1 (en) * 2009-05-04 2010-11-04 Abbott Biotechnology, Ltd. Stable high protein concentration formulations of human anti-tnf-alpha-antibodies
US20110054414A1 (en) * 2009-04-29 2011-03-03 Abbott Biotechnology Ltd. Automatic Injection Device
WO2011075578A1 (en) 2009-12-16 2011-06-23 Philip Bosch Methods of treating interstitial cystitis
US20110171227A1 (en) * 2006-04-10 2011-07-14 Okun Martin M Methods and compositions for treatment of skin disorders
US20110178500A1 (en) * 2009-12-15 2011-07-21 Shang Sherwin S Firing button for automatic injection device
WO2011153477A2 (en) 2010-06-03 2011-12-08 Abbott Biotechnology Ltd. Uses and compositions for treatment of hidradenitis suppurativa (hs)
US8162887B2 (en) 2004-06-23 2012-04-24 Abbott Biotechnology Ltd. Automatic injection devices
RU2470628C2 (en) * 2007-12-28 2012-12-27 Биоинвент Интернешнл Аб Formulation
WO2013009843A1 (en) * 2011-07-11 2013-01-17 Camas Incorporated Compositions against bacterial toxins
EP2666479A2 (en) 2006-04-10 2013-11-27 Abbott Biotechnology Ltd Uses and compositions for treatment of juvenile rheumatoid arthritis
EP2666480A2 (en) 2006-04-10 2013-11-27 Abbott Biotechnology Ltd Uses and compositions for treatment of Crohn's desease
WO2013186230A1 (en) * 2012-06-12 2013-12-19 Boehringer Ingelheim International Gmbh Pharmaceutical formulation for a therapeutic antibody
EP2676677A1 (en) * 2011-02-17 2013-12-25 Kyowa Hakko Kirin Co., Ltd. Highly concentrated anti-cd40 antibody pharmaceutical preparation
US8658773B2 (en) 2011-05-02 2014-02-25 Immunomedics, Inc. Ultrafiltration concentration of allotype selected antibodies for small-volume administration
US8753839B2 (en) 2007-08-08 2014-06-17 Abbvie Inc. Compositions and methods for crystallizing antibodies
WO2014114651A1 (en) * 2013-01-24 2014-07-31 Glaxosmithkline Intellectual Property Development Limited Tnf-alpha antigen-binding proteins
US8821865B2 (en) 2010-11-11 2014-09-02 Abbvie Biotechnology Ltd. High concentration anti-TNFα antibody liquid formulations
WO2014144960A2 (en) 2013-03-15 2014-09-18 Abbvie Biotherapeutics Inc. Fc variants
US8883146B2 (en) 2007-11-30 2014-11-11 Abbvie Inc. Protein formulations and methods of making same
US8921526B2 (en) 2013-03-14 2014-12-30 Abbvie, Inc. Mutated anti-TNFα antibodies and methods of their use
US8946395B1 (en) 2013-10-18 2015-02-03 Abbvie Inc. Purification of proteins using hydrophobic interaction chromatography
WO2015035044A2 (en) 2013-09-04 2015-03-12 Abbvie Biotherapeutics Inc. Fc VARIANTS WITH IMPROVED ANTIBODY-DEPENDENT CELL-MEDIATED CYTOTOXICITY
US9017687B1 (en) 2013-10-18 2015-04-28 Abbvie, Inc. Low acidic species compositions and methods for producing and using the same using displacement chromatography
US9062106B2 (en) 2011-04-27 2015-06-23 Abbvie Inc. Methods for controlling the galactosylation profile of recombinantly-expressed proteins
US9067990B2 (en) 2013-03-14 2015-06-30 Abbvie, Inc. Protein purification using displacement chromatography
US9085618B2 (en) 2013-10-18 2015-07-21 Abbvie, Inc. Low acidic species compositions and methods for producing and using the same
US9150645B2 (en) 2012-04-20 2015-10-06 Abbvie, Inc. Cell culture methods to reduce acidic species
US9181337B2 (en) 2013-10-18 2015-11-10 Abbvie, Inc. Modulated lysine variant species compositions and methods for producing and using the same
US9181572B2 (en) 2012-04-20 2015-11-10 Abbvie, Inc. Methods to modulate lysine variant distribution
US9193787B2 (en) 2012-04-20 2015-11-24 Abbvie Inc. Human antibodies that bind human TNF-alpha and methods of preparing the same
EP2946767A1 (en) * 2014-05-23 2015-11-25 Ares Trading S.A. Liquid pharmaceutical composition
US9206390B2 (en) 2012-09-02 2015-12-08 Abbvie, Inc. Methods to control protein heterogeneity
US9234033B2 (en) 2012-09-02 2016-01-12 Abbvie, Inc. Methods to control protein heterogeneity
US9249182B2 (en) 2012-05-24 2016-02-02 Abbvie, Inc. Purification of antibodies using hydrophobic interaction chromatography
US20160031982A1 (en) * 2012-09-07 2016-02-04 Coherus Biosciences, Inc. Stable Aqueous Formulations of Adalimumab
US9278131B2 (en) 2012-08-10 2016-03-08 Adocia Process for lowering the viscosity of highly concentrated protein solutions
US9279015B2 (en) 2006-04-10 2016-03-08 Robert L. Wong Methods for treatment of ankylosing spondylitis using TNF alpha antibodies
EP3003369A1 (en) * 2013-05-28 2016-04-13 Momenta Pharmaceuticals, Inc. Pharmaceutical compositions comprising pyrophosphate
EP3009450A1 (en) * 2011-07-19 2016-04-20 Glaxo Group Limited Liquid formulation comprising adalimumab and an acetate buffer
US9326935B2 (en) * 2013-11-08 2016-05-03 Eli Lilly And Company Atomoxetine solution
EP2892559A4 (en) * 2012-09-05 2016-05-11 Tracon Pharmaceuticals Inc Antibody formulations and uses thereof
US20160136280A1 (en) * 2013-06-24 2016-05-19 Hoffmann-La Roche Inc. Stable intravenous formulation
EP3053573A1 (en) * 2015-02-06 2016-08-10 Ares Trading S.A. Liquid pharmaceutical composition
US9480743B2 (en) 2010-12-28 2016-11-01 Hexal Ag Pharmaceutical formulation comprising a biopharmaceutical drug
US9493569B2 (en) 2005-03-31 2016-11-15 Chugai Seiyaku Kabushiki Kaisha Structural isomers of sc(Fv)2
US9499614B2 (en) 2013-03-14 2016-11-22 Abbvie Inc. Methods for modulating protein glycosylation profiles of recombinant protein therapeutics using monosaccharides and oligosaccharides
US9518122B2 (en) 2009-09-30 2016-12-13 Tracon Pharmaceuticals, Inc. Endoglin antibodies
US9550826B2 (en) 2013-11-15 2017-01-24 Abbvie Inc. Glycoengineered binding protein compositions
US9598667B2 (en) 2013-10-04 2017-03-21 Abbvie Inc. Use of metal ions for modulation of protein glycosylation profiles of recombinant proteins
US9610301B2 (en) 2008-01-15 2017-04-04 Abbvie Deutschland Gmbh & Co Kg Powdered protein compositions and methods of making same
US9878102B2 (en) 2011-01-24 2018-01-30 Abbvie Biotechnology Ltd. Automatic injection devices having overmolded gripping surfaces
US9926375B2 (en) 2014-11-12 2018-03-27 Tracon Pharmaceuticals, Inc. Anti-endoglin antibodies and uses thereof
US10005835B2 (en) 2013-04-29 2018-06-26 Sanofi Anti-IL-4/anti-IL-13 bispecific antibody formulations
US20180194843A1 (en) * 2003-02-10 2018-07-12 Biogen Ma Inc. Immunoglobulin formulation and method of preparation thereof
EP3360596A1 (en) 2010-04-21 2018-08-15 AbbVie Biotechnology Ltd. Wearable automatic injection device for controlled delivery of therapeutic agents
WO2018184693A1 (en) * 2017-04-07 2018-10-11 Ares Trading S.A. Liquid pharmaceutical composition
US10155820B2 (en) 2014-11-12 2018-12-18 Tracon Pharmaceuticals, Inc. Anti-endoglin antibodies and uses thereof
US10179811B2 (en) 2015-04-10 2019-01-15 Fresenius Kabi Deutschland Gmbh Methods of treating Crohn's disease or ulcerative colitis using an induction dosing regimen comprising anti-TNF-alpha antibody
US10307483B2 (en) 2016-10-21 2019-06-04 Amgen Inc. Pharmaceutical formulations and methods of making the same
US10322176B2 (en) 2002-03-01 2019-06-18 Immunomedics, Inc. Subcutaneous administration of anti-CD74 antibody for systemic lupus erythematosus
US10426832B2 (en) 2014-05-23 2019-10-01 Fresenius Kabi Deutschland Gmbh Liquid pharmaceutical composition
US10493152B2 (en) 2014-05-23 2019-12-03 Fresenius Kabi Deutschland Gmbh Adalimumab formulations
US10799597B2 (en) 2017-04-03 2020-10-13 Immunomedics, Inc. Subcutaneous administration of antibody-drug conjugates for cancer therapy
US11008389B2 (en) 2011-03-16 2021-05-18 Sanofi Uses of a dual V region antibody-like protein
US11071782B2 (en) 2016-04-20 2021-07-27 Coherus Biosciences, Inc. Method of filling a container with no headspace
US11180559B2 (en) 2005-03-03 2021-11-23 Immunomedics, Inc. Subcutaneous anti-HLA-DR monoclonal antibody for treatment of hematologic malignancies
US11229702B1 (en) 2015-10-28 2022-01-25 Coherus Biosciences, Inc. High concentration formulations of adalimumab
US11534402B2 (en) 2017-03-06 2022-12-27 Arecor Limited Liquid pharmaceutical composition
US11534403B2 (en) 2017-03-06 2022-12-27 Arecor Limited Liquid pharmaceutical composition
US11608357B2 (en) 2018-08-28 2023-03-21 Arecor Limited Stabilized antibody protein solutions
US11607451B2 (en) 2005-06-14 2023-03-21 Amgen Inc. Self-buffering antibody formulations
US11634485B2 (en) 2019-02-18 2023-04-25 Eli Lilly And Company Therapeutic antibody formulation

Families Citing this family (122)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040002451A1 (en) * 2002-06-20 2004-01-01 Bruce Kerwin Compositions of pegylated soluble tumor necrosis factor receptors and methods of preparing
TW200621282A (en) 2004-08-13 2006-07-01 Wyeth Corp Stabilizing formulations
JO3000B1 (en) 2004-10-20 2016-09-05 Genentech Inc Antibody Formulations.
GT200600031A (en) 2005-01-28 2006-08-29 ANTI-BETA ANTIBODY FORMULATION
AU2006259536A1 (en) * 2005-06-15 2006-12-28 Schering Corporation Anti-IGF1R antibody formulations
US9309316B2 (en) 2005-12-20 2016-04-12 Bristol-Myers Squibb Company Stable subcutaneous protein formulations and uses thereof
WO2008121301A1 (en) 2007-03-29 2008-10-09 Abbott Laboratories Crystalline anti-human il-12 antibodies
TW200902025A (en) * 2007-04-11 2009-01-16 Alcon Res Ltd Use of an inhibitor of TNF α plus an antihistamine to treat allergic rhinitis and allergic conjunctivitis
EP2808343B8 (en) 2007-12-26 2020-01-15 Xencor, Inc. Fc variants with altered binding to FcRn
WO2009083246A1 (en) * 2007-12-31 2009-07-09 Bayer Schering Pharma Aktiengesellschaft Antibodies to tnf alpha
MX2010011955A (en) 2008-04-29 2011-01-21 Abbott Lab Dual variable domain immunoglobulins and uses thereof.
US9035027B2 (en) 2008-06-03 2015-05-19 Abbvie Inc. Dual variable domain immunoglobulins and uses thereof
NZ589436A (en) 2008-06-03 2012-12-21 Abbott Lab Dual variable domain immunoglobulins and uses thereof
NZ590074A (en) 2008-07-08 2012-12-21 Abbott Lab Prostaglandin e2 dual variable domain immunoglobulins and uses thereof
WO2010062896A1 (en) * 2008-11-28 2010-06-03 Abbott Laboratories Stable antibody compositions and methods for stabilizing same
WO2011029823A1 (en) 2009-09-09 2011-03-17 Novartis Ag Monoclonal antibody reactive with cd63 when expressed at the surface of degranulated mast cells
JP5721722B2 (en) * 2009-10-01 2015-05-20 アルコン リサーチ， リミテッド Olopatadine composition and use thereof
AR078651A1 (en) 2009-10-15 2011-11-23 Abbott Lab IMMUNOGLOBULINS WITH DUAL VARIABLE DOMAIN AND USES OF THE SAME
UY32979A (en) 2009-10-28 2011-02-28 Abbott Lab IMMUNOGLOBULINS WITH DUAL VARIABLE DOMAIN AND USES OF THE SAME
FR2958646B1 (en) * 2010-04-07 2012-05-18 Adocia POLYSACCHARIDES COMPRISING FUNCTIONAL CARBOXYL GROUPS SUBSTITUTED WITH A HYDROPHOBIC ACID DERIVATIVE.
RU2012139181A (en) 2010-02-26 2014-04-10 Ново Нордиск А/С STABLE COMPOSITION CONTAINING ANTIBODY
CN105001335B (en) 2010-03-01 2019-10-25 拜耳医药保健有限公司 For the monoclonal antibody of the optimization of tissue factor approach restrainer (TFPI)
ES2564502T3 (en) 2010-03-17 2016-03-23 Novaliq Gmbh Pharmaceutical composition for the treatment of increased intraocular pressure
CN105055306B (en) 2010-05-28 2019-10-01 诺沃—诺迪斯克有限公司 Stable multi-dose compositions comprising antibody and preservative
AU2011285852B2 (en) 2010-08-03 2014-12-11 Abbvie Inc. Dual variable domain immunoglobulins and uses thereof
KR20130139884A (en) 2010-08-26 2013-12-23 애브비 인코포레이티드 Dual variable domain immunoglobulins and uses thereof
JP2013543384A (en) 2010-10-05 2013-12-05 ノバルティス アーゲー Anti-IL12Rbeta1 antibody and its use in the treatment of autoimmune and inflammatory diseases
EP2444063A1 (en) 2010-10-20 2012-04-25 Novaliq GmbH Liquid pharmaceutical compositions for the delivery of active ingredients
TWI698254B (en) * 2011-05-02 2020-07-11 美商千禧製藥公司 FORMULATION FOR ANTI-α4β7 ANTIBODY
AR087305A1 (en) 2011-07-28 2014-03-12 Regeneron Pharma STABILIZED FORMULATIONS CONTAINING ANTI-PCSK9 ANTIBODIES, PREPARATION METHOD AND KIT
PE20191242A1 (en) 2011-10-25 2019-09-16 Prothena Biosciences Ltd ANTIBODY FORMULATIONS AND METHODS
TW201333035A (en) 2011-12-30 2013-08-16 Abbvie Inc Dual specific binding proteins directed against IL-13 and/or IL-17
BR112014017719A8 (en) 2012-01-23 2017-07-11 Novaliq Gmbh STABILIZED PROTEIN COMPOSITIONS BASED ON SEMIFLUORINATED ALKANES
MX363700B (en) * 2012-03-07 2019-03-29 Cadila Healthcare Ltd Pharmaceutical formulations of tnf-alpha antibodies.
PT2830658T (en) * 2012-03-26 2018-12-28 Sanofi Sa Stable igg4 binding agent formulations
US9592289B2 (en) * 2012-03-26 2017-03-14 Sanofi Stable IgG4 based binding agent formulations
US9592297B2 (en) 2012-08-31 2017-03-14 Bayer Healthcare Llc Antibody and protein formulations
KR102158400B1 (en) 2012-09-12 2020-09-22 노바리크 게엠베하 Compositions comprising mixtures of semifluorinated alkanes
MX350588B (en) 2012-09-12 2017-09-11 Novaliq Gmbh Semifluorinated alkane compositions.
CA2889271A1 (en) * 2012-10-26 2014-05-01 Lupin Atlantis Holdings Sa Stable pharmaceutical composition of tnfr:fc fusion protein
KR20180008921A (en) 2012-11-01 2018-01-24 애브비 인코포레이티드 Anti-vegf/dll4 dual variable domain immunoglobulins and uses thereof
WO2014099636A1 (en) * 2012-12-18 2014-06-26 Merck Sharp & Dohme Corp. Liquid formulations for an anti-tnf alpha antibody
CN102988984B (en) * 2012-12-21 2015-05-20 嘉和生物药业有限公司 Aqueous drug preparation of anti-TNF (tumor necrosis factor)-alpha human monoclonal antibody for strengthening stability
UY35315A (en) 2013-02-08 2014-09-30 Novartis Ag ANTI-IL-17A ANTIBODIES AND ITS USE IN THE TREATMENT OF AUTOIMMUNE AND INFLAMMATORY DISORDERS
AU2014240431A1 (en) 2013-03-14 2015-08-27 Abbvie Inc. Low acidic species compositions and methods for producing the same using displacement chromatography
SG11201504260UA (en) 2013-03-14 2015-10-29 Abbvie Inc Low acidic species compositions and methods for producing and using the same
WO2014141149A1 (en) * 2013-03-15 2014-09-18 Glaxosmithkline Intellectual Property (No.2) Limited Formulations with reduced viscosity
CA2904448A1 (en) 2013-03-15 2014-09-18 Tariq Ghayur Dual specific binding proteins directed against il-1.beta. and/or il-17
CN103446583B (en) * 2013-03-21 2015-11-18 百奥泰生物科技(广州)有限公司 A kind of people's antibody preparation for the treatment of TNF-alpha associated disorders
WO2015007912A1 (en) 2013-07-19 2015-01-22 Hexal Ag Methods and formulations which allow the modulation of immune responses related to the administration of a biopharmaceutical drug
US10273298B2 (en) * 2013-07-23 2019-04-30 Novaliq Gmbh Stabilized antibody compositions
WO2015057910A1 (en) 2013-10-16 2015-04-23 Oncobiologics, Inc. Buffer formulations for enhanced antibody stability
JP6590803B2 (en) 2013-11-21 2019-10-16 ゲンマブ エー／エス Antibody-drug conjugate lyophilized formulation
CN104666242B (en) * 2013-11-26 2018-01-02 信达生物制药(苏州)有限公司 A kind of anti-TNF Alpha antibodies preparation of stabilization and application thereof
CN104707146B (en) * 2013-12-16 2019-04-16 浙江海正药业股份有限公司 A kind of pharmaceutical composition containing adalimumab
EP2960252A1 (en) * 2014-06-26 2015-12-30 Institut Pasteur Phospholipase for treatment of immunosuppression
WO2015151115A1 (en) 2014-04-02 2015-10-08 Intas Pharmaceuticals Limited Liquid pharmaceutical composition of adalimumab
CN105012949A (en) * 2014-04-28 2015-11-04 上海药明康德新药开发有限公司 Preparation of recombinant human anti-human TNF-alpha monoclonal antibody
US20170291939A1 (en) 2014-06-25 2017-10-12 Novartis Ag Antibodies specific for il-17a fused to hyaluronan binding peptide tags
US20170226552A1 (en) 2014-07-03 2017-08-10 Abbvie Inc. Methods for modulating protein glycosylation profiles of recombinant protein therapeutics using cobalt
WO2016007764A1 (en) 2014-07-09 2016-01-14 Abbvie Inc. Methods for modulating the glycosylation profile of recombinant proteins using non-commonly used sugars
TWI711629B (en) 2014-09-03 2020-12-01 德商包林格因蓋爾漢國際股份有限公司 Compound targeting il-23a and tnf-alpha and uses thereof
US9821059B2 (en) * 2014-10-17 2017-11-21 Alteogen Inc. Composition for stabilizing protein and pharmaceutical formulation comprising the same
HUP1400510A1 (en) 2014-10-28 2016-05-30 Richter Gedeon Nyrt Pharmaceutical anti-tnfalpha antibody formulation
US10093733B2 (en) 2014-12-11 2018-10-09 Abbvie Inc. LRP-8 binding dual variable domain immunoglobulin proteins
US20170360929A1 (en) * 2014-12-23 2017-12-21 Pfizer Inc. Stable aqueous antibody formulation for anti tnf alpha antibodies
US10696735B2 (en) 2015-01-21 2020-06-30 Outlook Therapeutics, Inc. Modulation of charge variants in a monoclonal antibody composition
WO2016162819A1 (en) 2015-04-07 2016-10-13 Lupin Limited Stable aqueous pharmaceutical composition of anti-tnf alpha antibody
TW201710286A (en) 2015-06-15 2017-03-16 艾伯維有限公司 Binding proteins against VEGF, PDGF, and/or their receptors
KR20180018538A (en) 2015-06-17 2018-02-21 제넨테크, 인크. Methods for the treatment of locally advanced or metastatic breast cancer using PD-1 axis-binding antagonists and taxanes
US20170028013A1 (en) * 2015-07-30 2017-02-02 Teva Pharmaceutical Industries, Ltd. Combination formulation of laquinimod and glatiramer acetate with amino acids
WO2017031151A1 (en) 2015-08-18 2017-02-23 Regeneron Pharmaceuticals, Inc. Anti-pcsk9 inhibitory antibodies for treating patients with hyperlipidemia undergoing lipoprotein apheresis
ES2803248T3 (en) 2015-09-30 2021-01-25 Novaliq Gmbh 2-perfluorohexyl octane for ophthalmic administration
PT3355990T (en) 2015-09-30 2019-09-11 Novaliq Gmbh Semifluorinated compounds and their compositions
US11583584B1 (en) * 2015-10-28 2023-02-21 Coherus Biosciences, Inc. Stable protein compositions and methods of their use
KR102386735B1 (en) * 2015-11-06 2022-04-14 주식회사 제넥신 Formulation for modified interleukin-7 fusion protein
US10988543B2 (en) 2015-11-11 2021-04-27 Opi Vi—Ip Holdco Llc Humanized anti-tumor necrosis factor alpha receptor 2 (anti-TNFR2) antibodies and methods of use thereof to elicit an immune response against a tumor
DK3380525T3 (en) * 2015-11-25 2024-01-29 Immunogen Inc PHARMACEUTICAL FORMULATIONS AND METHODS OF USING THEREOF
CN116003593A (en) 2016-01-11 2023-04-25 苏黎世大学 Immunostimulatory humanized monoclonal antibodies directed against human interleukin-2 and fusion proteins thereof
EP3402470A4 (en) * 2016-01-12 2019-11-13 Dr. Reddy's Laboratories Limited Stable pharmaceutical composition
EP3402465B1 (en) 2016-01-13 2024-03-13 Genmab A/S Formulation for antibody and drug conjugate thereof
CN109563161A (en) 2016-02-03 2019-04-02 安口生物公司 For improving the buffer preparation of Antibody stability
US20180043020A1 (en) * 2016-04-20 2018-02-15 Coherus Biosciences, Inc. Method of reducing immunogenicity of drug products
AU2017281296B2 (en) 2016-06-23 2021-03-11 Novaliq Gmbh Topical administration method
HUP1600456A2 (en) 2016-07-19 2018-01-29 Richter Gedeon Nyrt Novel cell-based tnf-alpha binding assay
KR102614858B1 (en) 2016-09-22 2023-12-18 노바리크 게엠베하 Pharmaceutical compositions used in the treatment of blepharitis
US10813976B2 (en) 2016-09-23 2020-10-27 Novaliq Gmbh Ophthalmic compositions comprising ciclosporin
JOP20190162A1 (en) 2016-12-30 2019-06-27 Biocad Joint Stock Co Aqueous Pharmaceutical Composition of a Recombinant Monoclonal Antibody to TNF?
AU2018207367B2 (en) 2017-01-11 2024-02-15 Celltrion Inc. Stable Liquid Formula
CN110678207A (en) 2017-04-21 2020-01-10 诺瓦利克有限责任公司 Iodine composition
CN106918633B (en) * 2017-04-24 2019-06-25 中国科学院苏州生物医学工程技术研究所 The detection method of cytokine TNF-α based on aptamer and golden magnetic nano particle
MX2019013072A (en) 2017-05-02 2019-12-16 Merck Sharp & Dohme Formulations of anti-lag3 antibodies and co-formulations of anti-lag3 antibodies and anti-pd-1 antibodies.
JOP20190260A1 (en) 2017-05-02 2019-10-31 Merck Sharp & Dohme Stable formulations of programmed death receptor 1 (pd-1) antibodies and methods of use thereof
CN110650734A (en) 2017-05-12 2020-01-03 诺瓦利克有限责任公司 Pharmaceutical compositions comprising semifluorinated alkanes for the treatment of conditions associated with contact lenses
US11136138B2 (en) 2017-07-10 2021-10-05 Autel Robotics Co., Ltd. Aircraft control method and apparatus and aircraft
WO2019057631A1 (en) 2017-09-20 2019-03-28 Alvotech Hf Pharmaceutical formulations for adalimumab
BR112020006072A2 (en) 2017-09-27 2020-10-06 Novaliq Gmbh ophthalmic compositions comprising latanoprost for use in the treatment of eye diseases
US11896559B2 (en) 2017-10-04 2024-02-13 Novaliq Gmbh Opthalmic compositions comprising F6H8
MX2017016884A (en) * 2017-12-19 2019-06-20 Probiomed S A De C V Stable pharmaceutical formulation of an anti-tnf? protein.
WO2019126133A1 (en) * 2017-12-20 2019-06-27 Alexion Pharmaceuticals, Inc. Liquid formulations of anti-cd200 antibodies
US11802154B2 (en) 2017-12-20 2023-10-31 Alexion Pharmaceuticals, Inc. Humanized anti-CD200 antibodies and uses thereof
CN108414479A (en) * 2018-01-19 2018-08-17 祝胜郎 A kind of purposes of immune composition in preparing IgA nephrosis Non-invasive detection reagents
WO2019147824A1 (en) 2018-01-26 2019-08-01 Progenity, Inc. Treatment of a disease of the gastrointestinal tract with a pde4 inhibitor
CN110151988A (en) * 2018-02-11 2019-08-23 百奥泰生物制药股份有限公司 A kind of human antibody preparation of targeted therapy TNF-α related disease
CN110302377B (en) * 2018-02-11 2020-04-17 百奥泰生物制药股份有限公司 Human antibody preparation for targeted therapy of TNF- α related diseases
EP3758676A1 (en) 2018-03-02 2021-01-06 Novaliq GmbH Pharmaceutical compositions comprising nebivolol
WO2019246271A1 (en) 2018-06-20 2019-12-26 Progenity, Inc. Treatment of a disease of the gastrointestinal tract with an il-12/il-23 inhibitor
US20230033021A1 (en) 2018-06-20 2023-02-02 Progenity, Inc. Treatment of a disease of the gastrointestinal tract with an integrin inhibitor
WO2019246313A1 (en) 2018-06-20 2019-12-26 Progenity, Inc. Treatment of a disease of the gastrointestinal tract with a tnf inhibitor
US20230009902A1 (en) 2018-06-20 2023-01-12 Progenity, Inc. Treatment of a disease or condition in a tissue orginating from the endoderm
US20220257600A1 (en) 2018-06-20 2022-08-18 Progenity, Inc. Treatment of a disease of the gastrointestinal tract with a jak or other kinase inhibitor
WO2019246312A1 (en) 2018-06-20 2019-12-26 Progenity, Inc. Treatment of a disease of the gastrointestinal tract with an immunomodulator
SG11202102820VA (en) 2018-10-12 2021-04-29 Novaliq Gmbh Ophthalmic composition for treatment of dry eye disease
WO2020138517A1 (en) * 2018-12-24 2020-07-02 삼성바이오에피스 주식회사 PHARMACOLOGICAL COMPOSITION COMPRISING ANTI-TNFα ANTIBODY
US11179473B2 (en) 2020-02-21 2021-11-23 Silverback Therapeutics, Inc. Nectin-4 antibody conjugates and uses thereof
JP2023522024A (en) * 2020-04-17 2023-05-26 ディンフー バイオターゲット カンパニー リミテッド Formulation that specifically binds to CD137 and its use
US20230173069A1 (en) * 2020-05-13 2023-06-08 Innovent Biologics (Suzhou) Co., Ltd. Formulation comprising anti-il-23p19 antibody, method for preparing same and use thereof
JP2023541765A (en) * 2020-06-29 2023-10-04 コディスカバリー・エルエルシー Cellular energy inhibitor formulations and related methods for the treatment of pathogenic infections
JP2023532304A (en) 2020-07-01 2023-07-27 エーアールエス ファーマシューティカルズ オペレーションズ，インク． Anti-ASGR1 antibody conjugates and uses thereof
WO2022231978A1 (en) * 2021-04-26 2022-11-03 Truebinding, Inc. Anti-gal3 antibody formulations and methods of use thereof
WO2023043232A1 (en) * 2021-09-16 2023-03-23 주식회사 에이프로젠 PHARMACEUTICAL COMPOSITION CONTAINING ANTI-TNFα ANTIBODY
US11773160B1 (en) 2022-08-05 2023-10-03 Anaveon AG Immune-stimulating IL-2 fusion proteins

Family Cites Families (157)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS605899B2 (en) 1975-04-10 1985-02-14 中外製薬株式会社 Immunochemical quantitative method
US4396608A (en) 1981-08-24 1983-08-02 Cutter Laboratories Intravenously injectable immune serum globulin
IE833023L (en) * 1983-01-28 1984-07-28 Joseph Patrick Mcauliffe System and process of identifying and updating tuning¹constants
EP0168506B2 (en) 1984-07-07 1998-01-07 Armour Pharma GmbH Process for preparing gamma globulin suitable for intravenous administration
IL73883A (en) 1984-12-20 1990-12-23 Yeda Res & Dev Monoclonal antibodies against tnf-alpha,hybridomas producing them and method for the purification of tnf-alpha
US4597966A (en) 1985-01-09 1986-07-01 Ortho Diagnostic Systems, Inc. Histidine stabilized immunoglobulin and method of preparation
US4870163A (en) 1985-08-29 1989-09-26 New York Blood Center, Inc. Preparation of pure human tumor necrosis factor and hybridomas producing monoclonal antibodies to human tumor necrosis factor
EP0230574A3 (en) 1986-01-31 1989-03-22 Yale University Pharmaceutical compositions against infections caused by lav/htlv iii virus and the use thereof
DE3631229A1 (en) 1986-09-13 1988-03-24 Basf Ag MONOCLONAL ANTIBODIES AGAINST HUMAN TUMORNESCROSE FACTOR (TNF) AND THEIR USE
US5237054A (en) 1987-02-20 1993-08-17 Akzo Pharma Stabilized aqueous composition containing antibodies
CA1329760C (en) 1987-10-29 1994-05-24 Ted C. K. Lee Plasma and recombinant protein formulations in high ionic strength media
US4877608A (en) 1987-11-09 1989-10-31 Rorer Pharmaceutical Corporation Pharmaceutical plasma protein formulations in low ionic strength media
US5981485A (en) 1997-07-14 1999-11-09 Genentech, Inc. Human growth hormone aqueous formulation
US5096885A (en) 1988-04-15 1992-03-17 Genentech, Inc. Human growth hormone formulation
WO1989011298A1 (en) 1988-05-27 1989-11-30 Centocor, Inc. Formulation for antibody reagents
EP0394385A1 (en) 1988-07-27 1990-10-31 BMC Software, Inc. Improved data transmission optimizer
US4897465A (en) 1988-10-12 1990-01-30 Abbott Laboratories Enrichment and concentration of proteins by ultrafiltration
SG43205A1 (en) 1988-12-19 1997-10-17 American Cyanamid Co A method for the treatment of endotoxic shock in a mammal
CA2049342A1 (en) 1989-03-27 1990-09-28 Sally Bolmer Formulations for stabilizing of igm antibodies
JP3443119B2 (en) 1989-08-07 2003-09-02 ペプテック リミテッド Tumor necrosis factor binding ligand
US5998378A (en) 1989-08-16 1999-12-07 Chiron Corporation Compositions for the inhibition of TNF hormone formation and uses thereof
GB8921123D0 (en) 1989-09-19 1989-11-08 Millar Ann B Treatment of ards
JPH0791318B2 (en) 1989-09-21 1995-10-04 三井東圧化学株式会社 Aqueous protein solution, method for increasing concentration of aqueous protein solution, and protein preparation
US5945098A (en) * 1990-02-01 1999-08-31 Baxter International Inc. Stable intravenously-administrable immune globulin preparation
AU646695B2 (en) 1990-04-09 1994-03-03 Immunex Corporation Isolated viral protein cytokine antagonists
DE4037604A1 (en) 1990-04-25 1991-10-31 Bayer Ag Use of anti-TNF antibodies to treat ischaemia and its sequelae - esp. to increase survival rate after myocardial infarct and transplants
JPH06500323A (en) 1990-08-27 1994-01-13 ペプチド　テクノロジィ　リミテッド How to treat viral infections
GB9109645D0 (en) 1991-05-03 1991-06-26 Celltech Ltd Recombinant antibodies
JPH0565233A (en) 1991-03-08 1993-03-19 Mitsui Toatsu Chem Inc Monoclonal antibody-containing lyophilized preparation
AU1674292A (en) 1991-03-15 1992-10-21 Synergen, Inc. Pegylation of polypeptides
US6277969B1 (en) 1991-03-18 2001-08-21 New York University Anti-TNF antibodies and peptides of human tumor necrosis factor
US20060246073A1 (en) 1991-03-18 2006-11-02 Knight David M Anti-TNF antibodies and peptides of human tumor necrosis factor
DE06001779T1 (en) 1991-03-18 2010-01-14 New York University Monoclonal and chimeric antibodies to human tumor necrosis factor
US6165467A (en) 1991-07-20 2000-12-26 Yoshihide Hagiwara Stabilized human monoclonal antibody preparation
GB9122820D0 (en) 1991-10-28 1991-12-11 Wellcome Found Stabilised antibodies
AU3244693A (en) 1991-12-17 1993-07-19 Schering Corporation Use of the combination of anti-tumor necrosis factor plus interleukin-6 to treat septic shock
DE69331265T2 (en) 1992-04-02 2002-08-08 Smithkline Beecham Corp COMPOUNDS FOR TREATING INFLAMMABLE DISEASES AND INHIBITING THE PRODUCTION OF TUMORNESCROSE FACTOR
DK0585705T3 (en) 1992-08-28 1999-07-26 Bayer Ag Use of monoclonal anti-TNF antibodies to treat bacterial meningitis
WO1994008609A1 (en) 1992-10-15 1994-04-28 Dana-Farber Cancer Institute, Inc. TREATMENT OF INSULIN RESISTANCE IN OBESITY LINKED TYPE II DIABETES USING ANTAGONISTS TO TNF-α FUNCTION
US5358708A (en) 1993-01-29 1994-10-25 Schering Corporation Stabilization of protein formulations
ATE204299T1 (en) 1993-03-05 2001-09-15 Bayer Ag HUMAN MONOCLONAL ANTI-TNF ALPHA ANTIBODIES
DE4307508A1 (en) 1993-03-10 1994-09-15 Knoll Ag Use of anti-TNF antibodies as a medicine in the treatment of heart failure (heart muscle weakness)
FR2708467B1 (en) 1993-07-30 1995-10-20 Pasteur Merieux Serums Vacc Stabilized immunoglobulin preparations and process for their preparation.
DE4344824C1 (en) 1993-12-28 1995-08-31 Immuno Ag Highly concentrated immunoglobulin preparation and process for its preparation
NZ278607A (en) 1994-02-07 1999-05-28 Knoll Ag Use of tnf antagonists for treating disorders involving elevated serum levels of il-6 wherein the serum levels are 500pg/ml or above
ZA955642B (en) 1994-07-07 1997-05-06 Ortho Pharma Corp Lyophilized imaging agent formulation
GB9418092D0 (en) 1994-09-08 1994-10-26 Red Cross Found Cent Lab Blood Organic compounds
US5656730A (en) 1995-04-07 1997-08-12 Enzon, Inc. Stabilized monomeric protein compositions
US6267958B1 (en) 1995-07-27 2001-07-31 Genentech, Inc. Protein formulation
DK1516628T3 (en) * 1995-07-27 2013-09-08 Genentech Inc Stable, isotonic lyophilized protein formulation
ATE234918T1 (en) 1995-08-04 2003-04-15 Lek Tovarna Farmacevtskih MONOCLONAL ANTIBODIES AGAINST SOLUBLE TNF-ALPHA RECEPTORS P55 AND P75 AS WELL AS AGAINST TNF-ALPHA AND ITS ANALOGUES
US6090382A (en) 1996-02-09 2000-07-18 Basf Aktiengesellschaft Human antibodies that bind human TNFα
US5770700A (en) 1996-01-25 1998-06-23 Genetics Institute, Inc. Liquid factor IX formulations
SK284040B6 (en) * 1996-02-09 2004-08-03 Abbott Laboratories (Bermuda) Ltd. Human antibodies that bind human TNFalpha
GB9610992D0 (en) * 1996-05-24 1996-07-31 Glaxo Group Ltd Concentrated antibody preparation
EP0938334A4 (en) 1996-07-26 2004-12-15 Smithkline Beecham Corp Improved method of treating immune cell mediated systemic diseases
EP0852951A1 (en) 1996-11-19 1998-07-15 Roche Diagnostics GmbH Stable lyophilized monoclonal or polyclonal antibodies containing pharmaceuticals
GB9705810D0 (en) 1997-03-20 1997-05-07 Common Services Agency Intravenous immune globulin
WO1998044948A2 (en) 1997-04-07 1998-10-15 Cangene Corporation Intravenous immune globulin formulation containing a non-ionic surface active agent with improved pharmacokinetic properties
US6171586B1 (en) * 1997-06-13 2001-01-09 Genentech, Inc. Antibody formulation
CA2635352C (en) * 1997-06-13 2012-09-11 Genentech, Inc. Stabilized antibody formulation
CN1149100C (en) 1997-10-23 2004-05-12 三菱制药株式会社 Room temperature storable immunoglobulin preparation for intravenous injection
PT917879E (en) 1997-11-22 2002-12-31 Roche Diagnostics Gmbh IMPROVED PROCESS FOR PROTEIN STABILIZATION
WO1999037329A1 (en) 1998-01-22 1999-07-29 Astrazeneca Ab Pharmaceutical formulation comprising an antibody and a citrate buffer
JP4685238B2 (en) 1998-06-09 2011-05-18 ツエー・エス・エル・ベーリング・アクチエンゲゼルシヤフト Process for the production of intravenous immunoglobulins and other immunoglobulin products
GB9819019D0 (en) 1998-09-01 1998-10-28 Cerebrus Ltd Chemical compounds II
US6379666B1 (en) 1999-02-24 2002-04-30 Edward L. Tobinick TNF inhibitors for the treatment of neurological, retinal and muscular disorders
US6177077B1 (en) 1999-02-24 2001-01-23 Edward L. Tobinick TNT inhibitors for the treatment of neurological disorders
US6423321B2 (en) 1999-02-24 2002-07-23 Edward L. Tobinick Cytokine antagonists for the treatment of sensorineural hearing loss
US6419934B1 (en) 1999-02-24 2002-07-16 Edward L. Tobinick TNF modulators for treating neurological disorders associated with viral infection
US6419944B2 (en) 1999-02-24 2002-07-16 Edward L. Tobinick Cytokine antagonists for the treatment of localized disorders
US6015557A (en) 1999-02-24 2000-01-18 Tobinick; Edward L. Tumor necrosis factor antagonists for the treatment of neurological disorders
US6537549B2 (en) 1999-02-24 2003-03-25 Edward L. Tobinick Cytokine antagonists for the treatment of localized disorders
PL218748B1 (en) 1999-03-25 2015-01-30 Abbott Gmbh & Co Kg Human antibodies that bind human il-12 and methods for producing
WO2000066160A1 (en) * 1999-04-28 2000-11-09 Yamanouchi Pharmaceutical Co., Ltd. Parenteral medicinal composition containing humanized monoclonal antibody fragment and method for stabilizing the same
EP1173217B1 (en) 1999-05-05 2005-10-19 Merrion Research I Limited Enhanced delivery of nucleic acid-based drugs
AUPQ026799A0 (en) 1999-05-10 1999-06-03 Csl Limited Method of increasing protein stability by removing immunoglobulin aggregates
MXPA01013458A (en) 1999-06-25 2002-07-30 Genentech Inc HUMANIZED ANTI-ErbB2 ANTIBODIES AND TREATMENT WITH ANTI-ErbB2 ANTIBODIES.
US20010031260A1 (en) 1999-12-14 2001-10-18 Genentech, Inc. Treatment method
JP4516711B2 (en) * 1999-12-28 2010-08-04 中外製薬株式会社 Stable antibody composition and injection preparation
US6585957B1 (en) 2000-01-25 2003-07-01 Aeropharm Technology Incorporated Medicinal aerosol formulation
US7495018B2 (en) 2000-03-30 2009-02-24 Takeda Pharmaceutical Company Limited Substituted 1,3-thiazole compounds, their production and use
DE10022092A1 (en) 2000-05-08 2001-11-15 Aventis Behring Gmbh Stabilized protein preparation and process for its preparation
AU750296B2 (en) 2000-06-23 2002-07-11 F. Hoffmann-La Roche Ag Antibodies against SEMP1, methods for their production and uses thereof
EP1336410A4 (en) 2000-08-04 2005-10-12 Chugai Pharmaceutical Co Ltd Protein injection preparations
UA81743C2 (en) * 2000-08-07 2008-02-11 Центокор, Инк. HUMAN MONOCLONAL ANTIBODY WHICH SPECIFICALLY BINDS TUMOR NECROSIS FACTOR ALFA (TNFα), PHARMACEUTICAL MIXTURE CONTAINING THEREOF, AND METHOD FOR TREATING ARTHRITIS
US6902734B2 (en) 2000-08-07 2005-06-07 Centocor, Inc. Anti-IL-12 antibodies and compositions thereof
DK1314437T3 (en) 2000-08-11 2014-07-14 Chugai Pharmaceutical Co Ltd Stabilized antibody-containing preparations
SE0003045D0 (en) 2000-08-29 2000-08-29 Probi Ab New method
IL155002A0 (en) 2000-10-12 2003-10-31 Genentech Inc Reduced-viscosity concentrated protein formulations
AU3664102A (en) 2000-12-01 2002-06-11 Battelle Memorial Institute Method for stabilizing biomolecules in liquid formulations
EP2325205A3 (en) 2000-12-28 2011-10-12 Altus Pharmaceuticals Inc. Crystals of whole antibodies and fragments thereof and methods for making and using them
ES2184594B1 (en) 2001-01-17 2004-01-01 Probitas Pharma Sa PROCEDURE FOR THE PRODUCTION OF GAMMAGLOBULINA G HUMANA INACTIVADA OF VIRUS.
KR20020066778A (en) 2001-02-13 2002-08-21 한국과학기술연구원 Formulation to enhance bioavailability of bioactive materials and preparation method thereof
US6850177B2 (en) 2001-05-14 2005-02-01 Xyron Corporation Digital to analog convertor
BR0206160A (en) 2001-05-25 2004-10-26 Abbott Gmbh & Co Kg Use of anti-TNF antibodies as medicines in the treatment of septic disorders of anemic patients.
JP5052736B2 (en) 2001-05-30 2012-10-17 中外製薬株式会社 Protein preparation
GB0113179D0 (en) 2001-05-31 2001-07-25 Novartis Ag Organic compounds
CA2385745C (en) 2001-06-08 2015-02-17 Abbott Laboratories (Bermuda) Ltd. Methods of administering anti-tnf.alpha. antibodies
JP4460892B2 (en) 2001-06-21 2010-05-12 ジェネンテック インコーポレイテッド Sustained release composition
US20030113316A1 (en) 2001-07-25 2003-06-19 Kaisheva Elizabet A. Stable lyophilized pharmaceutical formulation of IgG antibodies
US6818613B2 (en) 2001-11-07 2004-11-16 Ortho-Mcneil Pharmaceutical, Inc. Aqueous sustained-release formulations of proteins
EP1441589B1 (en) 2001-11-08 2012-05-09 Abbott Biotherapeutics Corp. Stable liquid pharmaceutical formulation of igg antibodies
GB0202633D0 (en) 2002-02-05 2002-03-20 Delta Biotechnology Ltd Stabilization of protein preparations
EP1475100B1 (en) 2002-02-14 2015-05-06 Chugai Seiyaku Kabushiki Kaisha Use of acetic acid for suppressing Fe ion induced problems in formulations of anti-HM1.24 or anti-IL6R antibodies
US20030161828A1 (en) 2002-02-19 2003-08-28 Abbott Gmbh & Co. Kg Use of TNF antagonists as drugs for the treatment of patients with an inflammatory reaction and without suffering from total organ failure
DK1946776T3 (en) 2002-02-27 2017-03-13 Immunex Corp STABILIZED TNFR-FC COMPOSITION COMPREHENSIVE ARGININE
US20030206898A1 (en) 2002-04-26 2003-11-06 Steven Fischkoff Use of anti-TNFalpha antibodies and another drug
US20040009172A1 (en) 2002-04-26 2004-01-15 Steven Fischkoff Use of anti-TNFalpha antibodies and another drug
CN1671741A (en) 2002-06-21 2005-09-21 拜奥根Idec公司 Buffered formulations for concentrating antibodies and methods of use thereof
US7601351B1 (en) 2002-06-26 2009-10-13 Human Genome Sciences, Inc. Antibodies against protective antigen
CA2492143A1 (en) 2002-07-12 2004-01-22 Medarex, Inc. Methods and compositions for preventing oxidative degradation of proteins
PL213925B1 (en) 2002-07-19 2013-05-31 Abbott Biotech Ltd Treatment of tnf ó related disorders
US20090280065A1 (en) 2006-04-10 2009-11-12 Willian Mary K Uses and Compositions for Treatment of Psoriasis
US20040033228A1 (en) * 2002-08-16 2004-02-19 Hans-Juergen Krause Formulation of human antibodies for treating TNF-alpha associated disorders
MY150740A (en) 2002-10-24 2014-02-28 Abbvie Biotechnology Ltd Low dose methods for treating disorders in which tnf? activity is detrimental
UY28126A1 (en) 2002-12-24 2004-06-30 Alcon Inc USE OF SELECTIVE GLUCOCORTICOIDS FOR THE EYE SURFACE IN THE TREATMENT OF EYE DROUGHT
MXPA05009135A (en) 2003-02-28 2005-10-20 Ares Trading Sa Liquid formulations of tumor necrosis factor-binding proteins.
DE602004003101T2 (en) 2003-04-25 2007-02-15 S.C. Johnson & Son, Inc., Racine DEVICE APPLIED TO THE EDGE OF A TOILET BASIN FOR DELIVERING TWO LIQUIDS
WO2005089755A1 (en) 2004-03-18 2005-09-29 R-Tech Ueno, Ltd. Aqueous composition comprising thiazole derivative
TWI439284B (en) 2004-04-09 2014-06-01 Abbvie Biotechnology Ltd Multiple-variable dose regimen for treating tnfα-related disorders
WO2006041970A2 (en) 2004-10-08 2006-04-20 Abbott Biotechnology Ltd. Treatment of respiratory syncytial virus (rsv) infection
KR101465456B1 (en) 2005-05-16 2014-11-27 애브비 바이오테크놀로지 리미티드 Use of TNF inhibitor for treatment of erosive polyarthritis
CA2610839C (en) 2005-06-14 2019-06-25 Amgen Inc. Self-buffering protein formulations
US20070041905A1 (en) 2005-08-19 2007-02-22 Hoffman Rebecca S Method of treating depression using a TNF-alpha antibody
US7919264B2 (en) 2005-11-01 2011-04-05 Abbott Biotechnology Ltd. Methods and compositions for determining the efficacy of a treatment for ankylosing spondylitis using biomarkers
KR20140071452A (en) 2006-04-05 2014-06-11 애브비 바이오테크놀로지 리미티드 Antibody purification
US20090317399A1 (en) 2006-04-10 2009-12-24 Pollack Paul F Uses and compositions for treatment of CROHN'S disease
WO2007120656A2 (en) 2006-04-10 2007-10-25 Abbott Biotechnology Ltd. Uses and compositions for treatment of rheumatoid arthritis
US20080118496A1 (en) 2006-04-10 2008-05-22 Medich John R Uses and compositions for treatment of juvenile rheumatoid arthritis
EP2012586A4 (en) 2006-04-10 2010-08-18 Abbott Biotech Ltd Uses and compositions for treatment of ankylosing spondylitis
EP2666472A3 (en) 2006-04-10 2014-04-02 Abbott Biotechnology Ltd Uses and compositions for treatment of psoriatic arthritis
US9605064B2 (en) 2006-04-10 2017-03-28 Abbvie Biotechnology Ltd Methods and compositions for treatment of skin disorders
US20080131374A1 (en) 2006-04-19 2008-06-05 Medich John R Uses and compositions for treatment of rheumatoid arthritis
US20080311043A1 (en) 2006-06-08 2008-12-18 Hoffman Rebecca S Uses and compositions for treatment of psoriatic arthritis
US20100021451A1 (en) 2006-06-08 2010-01-28 Wong Robert L Uses and compositions for treatment of ankylosing spondylitis
CA2651992A1 (en) 2006-06-30 2008-01-10 Abbott Biotechnology Ltd. Automatic injection device
ATE414518T1 (en) 2006-07-25 2008-12-15 Claus Herdeis PREPARATION OF ANTIMICROBIAL FORMULATIONS USING 7-OXA-2-THIA 1,5- DIAZABICYCLOÄ3.3.1UNONAN-2,2-DIONE
RU2518289C2 (en) 2006-09-13 2014-06-10 Эббви Инк, Method for preparing fed-batch antibody or its fragment (versions)
EP2684895A1 (en) 2006-10-27 2014-01-15 AbbVie Biotechnology Ltd Crystalline anti-hTNFalpha antibodies
EP2679995A1 (en) 2007-05-31 2014-01-01 AbbVie Inc. Biomarkers predictive of the responsiveness to TNF-alfa inhibitors in autoimmune disorders
WO2008150490A2 (en) 2007-06-01 2008-12-11 Abbott Biotechnology Ltd. Uses and compositions for treatment of psoriasis and crohn's disease
US8999337B2 (en) * 2007-06-11 2015-04-07 Abbvie Biotechnology Ltd. Methods for treating juvenile idiopathic arthritis by inhibition of TNFα
CN101848733A (en) 2007-07-13 2010-09-29 艾博特生物技术有限公司 The method and composition that is used for pulmonary administration TNF alpha inhibitor
WO2009020654A1 (en) 2007-08-08 2009-02-12 Abbott Laboratories Compositions and methods for crystallizing antibodies
CN101802005B (en) 2007-08-28 2015-09-16 艾伯维生物技术有限公司 Comprise the composition about the conjugated protein of adalimumab and method
US8883146B2 (en) 2007-11-30 2014-11-11 Abbvie Inc. Protein formulations and methods of making same
KR20190045414A (en) 2007-11-30 2019-05-02 애브비 바이오테크놀로지 리미티드 Protein formulations and methods of making same
EP2238446A4 (en) 2008-01-03 2011-07-20 Abbott Biotech Ltd Predicting long-term efficacy of a compound in the treatment of psoriasis
NZ621174A (en) 2008-01-15 2015-09-25 Abbvie Deutschland Powdered protein compositions and methods of making same
RU2502800C2 (en) 2008-01-15 2013-12-27 Эббви Инк. Improved expression vectors of mammals and their use
WO2009118662A2 (en) 2008-03-24 2009-10-01 Abbott Biotechnology Ltd. Methods and compositions for treating bone loss
CA2760237C (en) 2009-04-29 2017-11-14 Abbott Biotechnology Ltd. Automatic injection device and plunger for same
SG175188A1 (en) 2009-05-04 2011-11-28 Abbott Biotech Ltd Stable high protein concentration formulations of human anti-tnf-alpha-antibodies
ES2601202T3 (en) 2010-11-11 2017-02-14 Abbvie Biotechnology Ltd Liquid formulations of high concentration anti-TNT-alpha antibodies
MX363700B (en) 2012-03-07 2019-03-29 Cadila Healthcare Ltd Pharmaceutical formulations of tnf-alpha antibodies.
EA201791717A1 (en) 2012-09-07 2018-03-30 Кохерус Байосайенсис, Инк. STABLE WATER COMPOSITIONS ADALIMUMAB

Cited By (295)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070249813A1 (en) * 1996-02-09 2007-10-25 Salfeld Jochen G Human antibodies that bind human TNFa
US8206714B2 (en) 1996-02-09 2012-06-26 Abbott Biotechnology Ltd. Methods for treating rheumatoid arthritis using human antibodies that bind human TNFa
US8753633B2 (en) 1996-02-09 2014-06-17 Abbvie Biotechnology Ltd. Human antibodies that bind human TNFα
US7588761B2 (en) 1996-02-09 2009-09-15 Abbott Biotechnology Ltd. Human antibodies that bind human TNFα
US20100016557A1 (en) * 1996-02-09 2010-01-21 Abbott Biotechnology Ltd. HUMAN ANTIBODIES THAT BIND HUMAN TNFalpha
US20100040604A1 (en) * 1996-02-09 2010-02-18 Salfeld Jochen G HUMAN ANTIBODIES THAT BIND HUMAN TNFalpha
US8414894B2 (en) 1996-02-09 2013-04-09 Abbott Biotechnology Ltd. Human antibodies that bind human TNFα and methods of using same
US8197813B2 (en) 1996-02-09 2012-06-12 Abbott Biotechnology Ltd. Human antibodies that bind human TNFα
US7541031B2 (en) 1996-02-09 2009-06-02 Abbott Biotechnology Ltd. Methods for treating rheumatoid arthritis using human antibodies that bind human TNFα
US8372400B2 (en) 1996-02-09 2013-02-12 Abbott Biotechnology Ltd. Methods of treating disorders using human antibodies that bind human TNFα
US8372401B2 (en) 1996-02-09 2013-02-12 Abbott Biotechnology Ltd. Human antibodies that bind human TNFα
US20090155205A1 (en) * 1996-02-09 2009-06-18 Salfeld Jochen G HUMAN ANTIBODIES THAT BIND HUMAN TNFa
US8974790B2 (en) 2001-06-08 2015-03-10 Abbvie Biotechnology Ltd. Methods of administering anti-TNFα antibodies
US8992926B2 (en) 2001-06-08 2015-03-31 Abbvie Biotechnology Ltd. Methods of administering anti-TNFα antibodies
US9546212B2 (en) 2001-06-08 2017-01-17 Abbvie Biotechnology Ltd. Methods of administering anti-TNFα antibodies
US20030235585A1 (en) * 2001-06-08 2003-12-25 Fischkoff Steven A. Methods of administering anti-TNFalpha antibodies
US9017680B2 (en) 2001-06-08 2015-04-28 Abbvie Biotechnology Ltd. Methods of administering anti-TNFα antibodies
US8889135B2 (en) 2001-06-08 2014-11-18 Abbvie Biotechnology Ltd. Methods of administering anti-TNFα antibodies
US8911737B2 (en) 2001-06-08 2014-12-16 Abbvie Biotechnology Ltd. Methods of administering anti-TNFα antibodies
US9073987B2 (en) 2001-06-08 2015-07-07 Abbvie Biotechnology Ltd. Methods of administering anti-TNFα antibodies
US10322176B2 (en) 2002-03-01 2019-06-18 Immunomedics, Inc. Subcutaneous administration of anti-CD74 antibody for systemic lupus erythematosus
US20040009172A1 (en) * 2002-04-26 2004-01-15 Steven Fischkoff Use of anti-TNFalpha antibodies and another drug
US20070202104A1 (en) * 2002-07-19 2007-08-30 Abbott Laboratories S.A. Treatment of spondyloarthropathies using TNFalpha inhibitors
US9090689B1 (en) 2002-07-19 2015-07-28 Abbvie Biotechnology Ltd. Use of TNFα inhibitor for treatment of psoriasis
US9085620B1 (en) 2002-07-19 2015-07-21 Abbvie Biotechnology Ltd. Use of TNFα inhibitor for treatment of psoriatic arthritis
US20040126372A1 (en) * 2002-07-19 2004-07-01 Abbott Biotechnology Ltd. Treatment of TNFalpha related disorders
US8906373B2 (en) 2002-07-19 2014-12-09 Abbvie Biotechnology Ltd. Use of TNF-alpha inhibitor for treatment of psoriasis
US9220781B2 (en) 2002-08-16 2015-12-29 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US9302011B2 (en) 2002-08-16 2016-04-05 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-α associated disorders
US20060153846A1 (en) * 2002-08-16 2006-07-13 Hans-Juergen Krause Formulation of human antibodies for treating tnf-alpha associated disorders
US8940305B2 (en) 2002-08-16 2015-01-27 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-α associated disorders
US8932591B2 (en) 2002-08-16 2015-01-13 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-α associated disorders
US8916158B2 (en) 2002-08-16 2014-12-23 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-α associated disorders
US8916157B2 (en) 2002-08-16 2014-12-23 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-α associated disorders
US8911741B2 (en) 2002-08-16 2014-12-16 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-alpha associated disorders
US9114166B2 (en) 2002-08-16 2015-08-25 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-α associated disorders
US8802100B2 (en) 2002-08-16 2014-08-12 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-alpha associated disorders
US8802102B2 (en) 2002-08-16 2014-08-12 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-α associated disorders
US8802101B2 (en) 2002-08-16 2014-08-12 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-α associated disorders
US8795670B2 (en) 2002-08-16 2014-08-05 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-alpha associated disorders
US9272042B2 (en) 2002-08-16 2016-03-01 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US9272041B2 (en) 2002-08-16 2016-03-01 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US9289497B2 (en) 2002-08-16 2016-03-22 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US9295725B2 (en) 2002-08-16 2016-03-29 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US9327032B2 (en) 2002-08-16 2016-05-03 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US8216583B2 (en) 2002-08-16 2012-07-10 Abbott Biotechnology, Ltd. Formulation of human antibodies for treating TNF-α associated disorders
US9732152B2 (en) 2002-08-16 2017-08-15 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US9950066B2 (en) 2002-08-16 2018-04-24 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US9738714B2 (en) 2002-08-16 2017-08-22 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US9750808B2 (en) 2002-08-16 2017-09-05 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-alpha associated disorders
US20040166111A1 (en) * 2002-10-24 2004-08-26 Zehra Kaymakcalan Low dose methods for treating disorders in which TNFalpha activity is detrimental
US8846046B2 (en) 2002-10-24 2014-09-30 Abbvie Biotechnology Ltd. Low dose methods for treating disorders in which TNFα activity is detrimental
US20180194843A1 (en) * 2003-02-10 2018-07-12 Biogen Ma Inc. Immunoglobulin formulation and method of preparation thereof
US10954303B2 (en) * 2003-02-10 2021-03-23 Biogen Ma Inc. Immunoglobulin formulation and method of preparation thereof
US20070184050A1 (en) * 2003-12-25 2007-08-09 Kirin Beer Kabushiki Kaisha Stable water-based medicinal preparation containing antibody
WO2005063291A1 (en) * 2003-12-25 2005-07-14 Kirin Beer Kabushiki Kaisha Stable water-based medicinal preparation containing antibody
US20090304682A1 (en) * 2004-04-09 2009-12-10 Hoffman Rebecca S Multiple-variable dose regimen for treating TNFa-related disorders
US8961974B2 (en) 2004-04-09 2015-02-24 Abbvie Biotechnology Ltd. Multiple-variable dose regimen for treating TNFα-related disorders
US8986693B1 (en) 2004-04-09 2015-03-24 Abbvie Biotechnology Ltd. Use of TNFα inhibitor for treatment of psoriasis
US8889136B2 (en) 2004-04-09 2014-11-18 Abbvie Biotechnology Ltd. Multiple-variable dose regimen for treating TNFα-related disorders
US9512216B2 (en) 2004-04-09 2016-12-06 Abbvie Biotechnology Ltd. Use of TNFα inhibitor
US20060009385A1 (en) * 2004-04-09 2006-01-12 Abbott Biotechnology Ltd. Multiple-variable dose regimen for treating TNFalpha-related disorders
US9187559B2 (en) 2004-04-09 2015-11-17 Abbvie Biotechnology Ltd Multiple-variable dose regimen for treating idiopathic inflammatory bowel disease
US9061005B2 (en) 2004-04-09 2015-06-23 Abbvie Biotechnology Ltd Multiple-variable dose regimen for treating idiopathic inflammatory bowel disease
US8961973B2 (en) 2004-04-09 2015-02-24 Abbvie Biotechnology Ltd. Multiple-variable dose regimen for treating TNFα-related disorders
US9499615B2 (en) 2004-04-09 2016-11-22 Abbvie Biotechnology Ltd Multiple-variable dose regimen for treating idiopathic inflammatory bowel disease
US9017287B2 (en) 2004-06-23 2015-04-28 Abbvie Biotechnology Ltd Automatic injection devices
US8162887B2 (en) 2004-06-23 2012-04-24 Abbott Biotechnology Ltd. Automatic injection devices
US8668670B2 (en) 2004-06-23 2014-03-11 Abbvie Biotechnology Ltd Automatic injection devices
US20060083741A1 (en) * 2004-10-08 2006-04-20 Hoffman Rebecca S Treatment of respiratory syncytial virus (RSV) infection
US11180559B2 (en) 2005-03-03 2021-11-23 Immunomedics, Inc. Subcutaneous anti-HLA-DR monoclonal antibody for treatment of hematologic malignancies
US9493569B2 (en) 2005-03-31 2016-11-15 Chugai Seiyaku Kabushiki Kaisha Structural isomers of sc(Fv)2
US8715664B2 (en) 2005-05-16 2014-05-06 Abbvie Biotechnology Ltd. Use of human TNFα antibodies for treatment of erosive polyarthritis
US8808700B1 (en) 2005-05-16 2014-08-19 Abbvie Biotechnology Ltd. Use of TNF alpha inhibitor for treatment of erosive polyarthritis
US20070071747A1 (en) * 2005-05-16 2007-03-29 Hoffman Rebecca S Use of TNFalpha inhibitor for treatment of erosive polyarthritis
US9067992B2 (en) 2005-05-16 2015-06-30 Abbvie Biotechnology Ltd. Use of TNFα inhibitor for treatment of psoriatic arthritis
US8858935B2 (en) 2005-05-19 2014-10-14 Amgen Inc. Compositions and methods for increasing the stability of antibodies
US20060269543A1 (en) * 2005-05-19 2006-11-30 Amgen Inc. Compositions and methods for increasing the stability of antibodies
US9241994B2 (en) * 2005-06-10 2016-01-26 Chugai Seiyaku Kabushiki Kaisha Pharmaceutical compositions containing sc(Fv)2
US20090214535A1 (en) * 2005-06-10 2009-08-27 Chugai Seiyaku Kabushiki Kaisha Pharmaceutical Compositions Containing sc(Fv)2
US9777066B2 (en) 2005-06-10 2017-10-03 Chugai Seiyaku Kabushiki Kaisha Pharmaceutical compositions containing sc(Fv)2
US11607451B2 (en) 2005-06-14 2023-03-21 Amgen Inc. Self-buffering antibody formulations
US20070081996A1 (en) * 2005-08-19 2007-04-12 Hoffman Rebecca S Method of treating depression using a TNFalpha antibody
US20070041905A1 (en) * 2005-08-19 2007-02-22 Hoffman Rebecca S Method of treating depression using a TNF-alpha antibody
US7919264B2 (en) 2005-11-01 2011-04-05 Abbott Biotechnology Ltd. Methods and compositions for determining the efficacy of a treatment for ankylosing spondylitis using biomarkers
US20070172897A1 (en) * 2005-11-01 2007-07-26 Maksymowych Walter P Methods and compositions for diagnosing ankylosing spondylitis using biomarkers
US9086418B2 (en) 2005-11-01 2015-07-21 Abbvie Biotechnology Ltd. Methods and compositions for diagnosing ankylosing spondylitis using biomarkers
WO2007072380A2 (en) * 2005-12-19 2007-06-28 Koninklijke Philips Electronics N.V. Method of making dried particles
WO2007072380A3 (en) * 2005-12-19 2007-10-11 Koninkl Philips Electronics Nv Method of making dried particles
US20080257021A1 (en) * 2005-12-19 2008-10-23 Koninklijke Philips Electronics, N.V. Method of Making Dried Particles
EP1798504A1 (en) * 2005-12-19 2007-06-20 Koninklijke Philips Electronics N.V. Method of making dried particles
US8906372B2 (en) 2006-04-05 2014-12-09 Abbvie Biotechnology Ltd. Purified antibody composition
US8883156B2 (en) 2006-04-05 2014-11-11 Abbvie Biotechnology Ltd. Purified antibody composition
US9273132B2 (en) 2006-04-05 2016-03-01 Abbvie Biotechnology Ltd Purified antibody composition
US20110002935A1 (en) * 2006-04-05 2011-01-06 Min Wan Antibody purification
US9913902B2 (en) 2006-04-05 2018-03-13 Abbvie Biotechnology Ltd. Purified antibody composition
US20070292442A1 (en) * 2006-04-05 2007-12-20 Min Wan Antibody purification
US8231876B2 (en) 2006-04-05 2012-07-31 Abbott Biotechnology Ltd. Purified antibody composition
US11083792B2 (en) 2006-04-05 2021-08-10 Abbvie Biotechnology Ltd Purified antibody composition
US9096666B2 (en) 2006-04-05 2015-08-04 Abbvie Biotechnology Ltd Purified antibody composition
US9102723B2 (en) 2006-04-05 2015-08-11 Abbvie Biotechnology Ltd Purified antibody composition
US8916153B2 (en) 2006-04-05 2014-12-23 Abbvie Biotechnology Ltd. Purified antibody composition
US7863426B2 (en) 2006-04-05 2011-01-04 Abbott Biotechnology Ltd. Antibody purification
US8895009B2 (en) 2006-04-05 2014-11-25 Abbvie Biotechnology Ltd. Purified antibody composition
US9328165B2 (en) 2006-04-05 2016-05-03 Abbvie Biotechnology Ltd. Purified antibody composition
EP2703010A2 (en) 2006-04-10 2014-03-05 Abbott Biotechnology Ltd. Uses and compositions for treatment of rheumatoid arthritis
US9279015B2 (en) 2006-04-10 2016-03-08 Robert L. Wong Methods for treatment of ankylosing spondylitis using TNF alpha antibodies
US9399061B2 (en) 2006-04-10 2016-07-26 Abbvie Biotechnology Ltd Methods for determining efficacy of TNF-α inhibitors for treatment of rheumatoid arthritis
US20090317399A1 (en) * 2006-04-10 2009-12-24 Pollack Paul F Uses and compositions for treatment of CROHN'S disease
WO2008063213A2 (en) 2006-04-10 2008-05-29 Abbott Biotechnology Ltd. Uses and compositions for treatment of psoriatic arthritis
EP2666478A2 (en) 2006-04-10 2013-11-27 Abbott Biotechnology Ltd Uses and compositions for treatment of psoriasis
US20080166348A1 (en) * 2006-04-10 2008-07-10 Hartmut Kupper Uses and compositions for treatment of rheumatoid arthritis
EP2666472A2 (en) 2006-04-10 2013-11-27 Abbott Biotechnology Ltd Uses and compositions for treatment of psoriatic arthritis
EP2708242A2 (en) 2006-04-10 2014-03-19 Abbott Biotechnology Ltd Uses and compositions for treatment of ankylosing spondylitis
EP2666480A2 (en) 2006-04-10 2013-11-27 Abbott Biotechnology Ltd Uses and compositions for treatment of Crohn's desease
EP2666479A2 (en) 2006-04-10 2013-11-27 Abbott Biotechnology Ltd Uses and compositions for treatment of juvenile rheumatoid arthritis
US20110171227A1 (en) * 2006-04-10 2011-07-14 Okun Martin M Methods and compositions for treatment of skin disorders
US9624295B2 (en) 2006-04-10 2017-04-18 Abbvie Biotechnology Ltd. Uses and compositions for treatment of psoriatic arthritis
US9605064B2 (en) 2006-04-10 2017-03-28 Abbvie Biotechnology Ltd Methods and compositions for treatment of skin disorders
US20080118496A1 (en) * 2006-04-10 2008-05-22 Medich John R Uses and compositions for treatment of juvenile rheumatoid arthritis
US20090280065A1 (en) * 2006-04-10 2009-11-12 Willian Mary K Uses and Compositions for Treatment of Psoriasis
US20080131374A1 (en) * 2006-04-19 2008-06-05 Medich John R Uses and compositions for treatment of rheumatoid arthritis
US8926975B2 (en) 2006-06-08 2015-01-06 Abbvie Biotechnology Ltd Method of treating ankylosing spondylitis
US20080311043A1 (en) * 2006-06-08 2008-12-18 Hoffman Rebecca S Uses and compositions for treatment of psoriatic arthritis
US20100021451A1 (en) * 2006-06-08 2010-01-28 Wong Robert L Uses and compositions for treatment of ankylosing spondylitis
US20100160894A1 (en) * 2006-06-30 2010-06-24 Julian Joseph F Automatic injection device
US9486584B2 (en) 2006-06-30 2016-11-08 Abbvie Biotechnology Ltd. Automatic injection device
US8679061B2 (en) * 2006-06-30 2014-03-25 Abbvie Biotechnology Ltd Automatic injection device
US20080112953A1 (en) * 2006-10-06 2008-05-15 Amgen Inc. Stable formulations
US8241632B2 (en) 2006-10-20 2012-08-14 Amgen Inc. Stable polypeptide formulations
US7705132B2 (en) 2006-10-20 2010-04-27 Amgen Inc. Stable polypeptide formulations
US20080124326A1 (en) * 2006-10-20 2008-05-29 Amgen Inc. Stable polypeptide formulations
US20100158908A1 (en) * 2006-10-20 2010-06-24 Amgen Inc. Stable Polypeptide Formulations
US8436149B2 (en) 2006-10-27 2013-05-07 Abbvie Biotechnology Ltd Crystalline anti-hTNFalpha antibodies
US8772458B2 (en) 2006-10-27 2014-07-08 Abbvie Biotechnology Ltd Crystalline anti-hTNFalpha antibodies
US20100034823A1 (en) * 2006-10-27 2010-02-11 Borhani David W Crystalline anti-hTNFalpha antibodies
US8034906B2 (en) 2006-10-27 2011-10-11 Abbott Biotechnology Ltd. Crystalline anti-hTNFalpha antibodies
US20090017472A1 (en) * 2007-05-31 2009-01-15 Bruno Stuhlmuller BIOMARKERS PREDICTIVE OF THE RESPONSIVENESS TO TNFalpha INHIBITORS IN AUTOIMMUNE DISORDERS
US8092998B2 (en) 2007-05-31 2012-01-10 Abbott Laboratories Biomarkers predictive of the responsiveness to TNFα inhibitors in autoimmune disorders
WO2008154543A2 (en) 2007-06-11 2008-12-18 Abbott Biotechnology Ltd. Methods for treating juvenile idiopathic arthritis
US9284370B1 (en) 2007-06-11 2016-03-15 Abbvie Biotechnology Ltd. Methods for treating juvenile idiopathic arthritis
US8999337B2 (en) 2007-06-11 2015-04-07 Abbvie Biotechnology Ltd. Methods for treating juvenile idiopathic arthritis by inhibition of TNFα
US9669093B2 (en) 2007-06-11 2017-06-06 Abbvie Biotechnology Ltd Methods for treating juvenile idiopathic arthritis
US20090258018A1 (en) * 2007-06-11 2009-10-15 Medich John R Methods for treating juvenile idiopathic arthritis
US20090110679A1 (en) * 2007-07-13 2009-04-30 Luk-Chiu Li Methods and compositions for pulmonary administration of a TNFa inhibitor
US8753839B2 (en) 2007-08-08 2014-06-17 Abbvie Inc. Compositions and methods for crystallizing antibodies
US8883146B2 (en) 2007-11-30 2014-11-11 Abbvie Inc. Protein formulations and methods of making same
EP2231175A4 (en) * 2007-11-30 2014-07-16 Abbvie Inc Protein formulations and methods of making same
EP3189831A1 (en) * 2007-11-30 2017-07-12 AbbVie Biotechnology Ltd Protein formulations and methods of making same
US11167030B2 (en) 2007-11-30 2021-11-09 Abbvie Biotechnology Ltd Protein formulations and methods of making same
RU2659431C2 (en) * 2007-11-30 2018-07-02 Эббви Байотекнолоджи Лтд. Protein compositions and methods for production thereof
EP2231175A2 (en) 2007-11-30 2010-09-29 Abbott Laboratories Protein formulations and methods of making same
US11191834B2 (en) 2007-11-30 2021-12-07 Abbvie Biotechnology Ltd Protein formulations and methods of making same
US9085619B2 (en) 2007-11-30 2015-07-21 Abbvie Biotechnology Ltd. Anti-TNF antibody formulations
US8420081B2 (en) 2007-11-30 2013-04-16 Abbvie, Inc. Antibody formulations and methods of making same
RU2470628C2 (en) * 2007-12-28 2012-12-27 Биоинвент Интернешнл Аб Formulation
US20090271164A1 (en) * 2008-01-03 2009-10-29 Peng Joanna Z Predicting long-term efficacy of a compound in the treatment of psoriasis
US9610301B2 (en) 2008-01-15 2017-04-04 Abbvie Deutschland Gmbh & Co Kg Powdered protein compositions and methods of making same
EP2918602A1 (en) 2009-04-16 2015-09-16 AbbVie Biotherapeutics Inc. Anti-TNF-alpha antibodies and their uses
US20100266613A1 (en) * 2009-04-16 2010-10-21 Harding Fiona A Anti-tnf-alpha antibodies and their uses
US8722860B2 (en) 2009-04-16 2014-05-13 Abbvie Biotherapeutics Inc. Anti-TNF-α antibodies and their uses
US20110054414A1 (en) * 2009-04-29 2011-03-03 Abbott Biotechnology Ltd. Automatic Injection Device
US8636704B2 (en) 2009-04-29 2014-01-28 Abbvie Biotechnology Ltd Automatic injection device
US20100278822A1 (en) * 2009-05-04 2010-11-04 Abbott Biotechnology, Ltd. Stable high protein concentration formulations of human anti-tnf-alpha-antibodies
US9944714B2 (en) 2009-09-30 2018-04-17 Tracon Pharmaceuticals, Inc. Endoglin antibodies
US9518122B2 (en) 2009-09-30 2016-12-13 Tracon Pharmaceuticals, Inc. Endoglin antibodies
US20110178500A1 (en) * 2009-12-15 2011-07-21 Shang Sherwin S Firing button for automatic injection device
US8758301B2 (en) 2009-12-15 2014-06-24 Abbvie Biotechnology Ltd Firing button for automatic injection device
US20110150891A1 (en) * 2009-12-16 2011-06-23 Philip Bosch Methods of Treating Interstitial Cystitis
WO2011075578A1 (en) 2009-12-16 2011-06-23 Philip Bosch Methods of treating interstitial cystitis
EP3360596A1 (en) 2010-04-21 2018-08-15 AbbVie Biotechnology Ltd. Wearable automatic injection device for controlled delivery of therapeutic agents
US9334320B2 (en) 2010-06-03 2016-05-10 Abbvie Biotechnology Ltd. Methods of treating moderate to severe hidradenitis suppurativa with anti-TNFalpha antibody
US8747854B2 (en) 2010-06-03 2014-06-10 Abbvie Biotechnology Ltd. Methods of treating moderate to severe hidradenitis suppurativa with anti-TNF-alpha antibodies
WO2011153477A2 (en) 2010-06-03 2011-12-08 Abbott Biotechnology Ltd. Uses and compositions for treatment of hidradenitis suppurativa (hs)
US8821865B2 (en) 2010-11-11 2014-09-02 Abbvie Biotechnology Ltd. High concentration anti-TNFα antibody liquid formulations
EP2658575B1 (en) * 2010-12-28 2017-11-15 Hexal AG Pharmaceutical formulation comprising a biopharmaceutical drug
US9480743B2 (en) 2010-12-28 2016-11-01 Hexal Ag Pharmaceutical formulation comprising a biopharmaceutical drug
US9878102B2 (en) 2011-01-24 2018-01-30 Abbvie Biotechnology Ltd. Automatic injection devices having overmolded gripping surfaces
US11565048B2 (en) 2011-01-24 2023-01-31 Abbvie Biotechnology Ltd. Automatic injection devices having overmolded gripping surfaces
EP2676677A1 (en) * 2011-02-17 2013-12-25 Kyowa Hakko Kirin Co., Ltd. Highly concentrated anti-cd40 antibody pharmaceutical preparation
US9125893B2 (en) 2011-02-17 2015-09-08 Kyowa Hakko Kirin Co., Ltd. Highly concentrated anti-CD40 antibody pharmaceutical preparation
EP2676677A4 (en) * 2011-02-17 2015-02-11 Kyowa Hakko Kirin Co Ltd Highly concentrated anti-cd40 antibody pharmaceutical preparation
US11008389B2 (en) 2011-03-16 2021-05-18 Sanofi Uses of a dual V region antibody-like protein
US9090688B2 (en) 2011-04-27 2015-07-28 Abbvie Inc. Methods for controlling the galactosylation profile of recombinantly-expressed proteins
US9365645B1 (en) 2011-04-27 2016-06-14 Abbvie, Inc. Methods for controlling the galactosylation profile of recombinantly-expressed proteins
US9505834B2 (en) 2011-04-27 2016-11-29 Abbvie Inc. Methods for controlling the galactosylation profile of recombinantly-expressed proteins
US9062106B2 (en) 2011-04-27 2015-06-23 Abbvie Inc. Methods for controlling the galactosylation profile of recombinantly-expressed proteins
US9255143B2 (en) 2011-04-27 2016-02-09 Abbvie Inc. Methods for controlling the galactosylation profile of recombinantly-expressed proteins
US9683050B2 (en) 2011-05-02 2017-06-20 Immunomedics, Inc. Stable compositions of high-concentration allotype-selected antibodies for small-volume administration
US8658773B2 (en) 2011-05-02 2014-02-25 Immunomedics, Inc. Ultrafiltration concentration of allotype selected antibodies for small-volume administration
US9963516B2 (en) 2011-05-02 2018-05-08 Immunomedics, Inc. Stable compositions of high-concentration allotype-selected antibodies for small-volume administration
US9468689B2 (en) 2011-05-02 2016-10-18 Immunomedics, Inc. Ultrafiltration concentration of allotype selected antibodies for small-volume administration
US9180205B2 (en) 2011-05-02 2015-11-10 Immunomedics, Inc. Stable compositions of high-concentration allotype-selected antibodies for small-volume administration
WO2013009843A1 (en) * 2011-07-11 2013-01-17 Camas Incorporated Compositions against bacterial toxins
US8926980B2 (en) 2011-07-11 2015-01-06 Camas Incorporated Compositions against bacterial toxins
EP3009450A1 (en) * 2011-07-19 2016-04-20 Glaxo Group Limited Liquid formulation comprising adalimumab and an acetate buffer
US9505833B2 (en) 2012-04-20 2016-11-29 Abbvie Inc. Human antibodies that bind human TNF-alpha and methods of preparing the same
US9150645B2 (en) 2012-04-20 2015-10-06 Abbvie, Inc. Cell culture methods to reduce acidic species
US9181572B2 (en) 2012-04-20 2015-11-10 Abbvie, Inc. Methods to modulate lysine variant distribution
US9346879B2 (en) 2012-04-20 2016-05-24 Abbvie Inc. Protein purification methods to reduce acidic species
US9708400B2 (en) 2012-04-20 2017-07-18 Abbvie, Inc. Methods to modulate lysine variant distribution
US9683033B2 (en) 2012-04-20 2017-06-20 Abbvie, Inc. Cell culture methods to reduce acidic species
US9334319B2 (en) 2012-04-20 2016-05-10 Abbvie Inc. Low acidic species compositions
US9193787B2 (en) 2012-04-20 2015-11-24 Abbvie Inc. Human antibodies that bind human TNF-alpha and methods of preparing the same
US9957318B2 (en) 2012-04-20 2018-05-01 Abbvie Inc. Protein purification methods to reduce acidic species
US9359434B2 (en) 2012-04-20 2016-06-07 Abbvie, Inc. Cell culture methods to reduce acidic species
US9249182B2 (en) 2012-05-24 2016-02-02 Abbvie, Inc. Purification of antibodies using hydrophobic interaction chromatography
WO2013186230A1 (en) * 2012-06-12 2013-12-19 Boehringer Ingelheim International Gmbh Pharmaceutical formulation for a therapeutic antibody
US9278131B2 (en) 2012-08-10 2016-03-08 Adocia Process for lowering the viscosity of highly concentrated protein solutions
US9512214B2 (en) 2012-09-02 2016-12-06 Abbvie, Inc. Methods to control protein heterogeneity
US9206390B2 (en) 2012-09-02 2015-12-08 Abbvie, Inc. Methods to control protein heterogeneity
US9234033B2 (en) 2012-09-02 2016-01-12 Abbvie, Inc. Methods to control protein heterogeneity
US9290568B2 (en) 2012-09-02 2016-03-22 Abbvie, Inc. Methods to control protein heterogeneity
US10195281B2 (en) 2012-09-05 2019-02-05 Tracon Pharmaceuticals, Inc. Antibody formulations and uses thereof
KR101820582B1 (en) * 2012-09-05 2018-01-22 트라콘 파마수티칼즈, 인코포레이티드 Antibody formulations and uses thereof
EP2892559A4 (en) * 2012-09-05 2016-05-11 Tracon Pharmaceuticals Inc Antibody formulations and uses thereof
US10159733B2 (en) 2012-09-07 2018-12-25 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US10716853B2 (en) 2012-09-07 2020-07-21 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US10159732B2 (en) 2012-09-07 2018-12-25 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US10155039B2 (en) 2012-09-07 2018-12-18 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US10207000B2 (en) 2012-09-07 2019-02-19 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US10286071B2 (en) 2012-09-07 2019-05-14 Coherus Biosciences, Inc. Syringe containing stable aqueous formulations of adalimumab
US10286072B2 (en) 2012-09-07 2019-05-14 Coherus Biosciences, Inc. Methods of manufacturing stable aqueous formulations of adalimumab
US10716854B2 (en) 2012-09-07 2020-07-21 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US10799585B2 (en) 2012-09-07 2020-10-13 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US9808525B2 (en) * 2012-09-07 2017-11-07 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US10688183B2 (en) 2012-09-07 2020-06-23 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US10772960B2 (en) 2012-09-07 2020-09-15 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US10722579B2 (en) 2012-09-07 2020-07-28 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US10772959B2 (en) 2012-09-07 2020-09-15 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US20160031982A1 (en) * 2012-09-07 2016-02-04 Coherus Biosciences, Inc. Stable Aqueous Formulations of Adalimumab
US10195275B2 (en) 2012-09-07 2019-02-05 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US10716852B2 (en) 2012-09-07 2020-07-21 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US10780163B2 (en) 2012-09-07 2020-09-22 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
US10786566B2 (en) 2012-09-07 2020-09-29 Coherus Biosciences, Inc. Stable aqueous formulations of adalimumab
WO2014114651A1 (en) * 2013-01-24 2014-07-31 Glaxosmithkline Intellectual Property Development Limited Tnf-alpha antigen-binding proteins
US9499614B2 (en) 2013-03-14 2016-11-22 Abbvie Inc. Methods for modulating protein glycosylation profiles of recombinant protein therapeutics using monosaccharides and oligosaccharides
US9708399B2 (en) 2013-03-14 2017-07-18 Abbvie, Inc. Protein purification using displacement chromatography
US9067990B2 (en) 2013-03-14 2015-06-30 Abbvie, Inc. Protein purification using displacement chromatography
US8921526B2 (en) 2013-03-14 2014-12-30 Abbvie, Inc. Mutated anti-TNFα antibodies and methods of their use
WO2014144960A2 (en) 2013-03-15 2014-09-18 Abbvie Biotherapeutics Inc. Fc variants
US10005835B2 (en) 2013-04-29 2018-06-26 Sanofi Anti-IL-4/anti-IL-13 bispecific antibody formulations
EP3003369A1 (en) * 2013-05-28 2016-04-13 Momenta Pharmaceuticals, Inc. Pharmaceutical compositions comprising pyrophosphate
EP3003369A4 (en) * 2013-05-28 2017-04-26 Momenta Pharmaceuticals, Inc. Pharmaceutical compositions comprising pyrophosphate
US20160136280A1 (en) * 2013-06-24 2016-05-19 Hoffmann-La Roche Inc. Stable intravenous formulation
WO2015035044A2 (en) 2013-09-04 2015-03-12 Abbvie Biotherapeutics Inc. Fc VARIANTS WITH IMPROVED ANTIBODY-DEPENDENT CELL-MEDIATED CYTOTOXICITY
US9598667B2 (en) 2013-10-04 2017-03-21 Abbvie Inc. Use of metal ions for modulation of protein glycosylation profiles of recombinant proteins
US9499616B2 (en) 2013-10-18 2016-11-22 Abbvie Inc. Modulated lysine variant species compositions and methods for producing and using the same
US8946395B1 (en) 2013-10-18 2015-02-03 Abbvie Inc. Purification of proteins using hydrophobic interaction chromatography
US9085618B2 (en) 2013-10-18 2015-07-21 Abbvie, Inc. Low acidic species compositions and methods for producing and using the same
US9181337B2 (en) 2013-10-18 2015-11-10 Abbvie, Inc. Modulated lysine variant species compositions and methods for producing and using the same
US9522953B2 (en) 2013-10-18 2016-12-20 Abbvie, Inc. Low acidic species compositions and methods for producing and using the same
US9315574B2 (en) 2013-10-18 2016-04-19 Abbvie, Inc. Low acidic species compositions and methods for producing and using the same
US9017687B1 (en) 2013-10-18 2015-04-28 Abbvie, Inc. Low acidic species compositions and methods for producing and using the same using displacement chromatography
US9688752B2 (en) 2013-10-18 2017-06-27 Abbvie Inc. Low acidic species compositions and methods for producing and using the same using displacement chromatography
US9200069B2 (en) 2013-10-18 2015-12-01 Abbvie, Inc. Low acidic species compositions and methods for producing and using the same
US9200070B2 (en) 2013-10-18 2015-12-01 Abbvie, Inc. Low acidic species compositions and methods for producing and using the same
US9266949B2 (en) 2013-10-18 2016-02-23 Abbvie, Inc. Low acidic species compositions and methods for producing and using the same
US9326935B2 (en) * 2013-11-08 2016-05-03 Eli Lilly And Company Atomoxetine solution
US9550826B2 (en) 2013-11-15 2017-01-24 Abbvie Inc. Glycoengineered binding protein compositions
US10493152B2 (en) 2014-05-23 2019-12-03 Fresenius Kabi Deutschland Gmbh Adalimumab formulations
EP2946767A1 (en) * 2014-05-23 2015-11-25 Ares Trading S.A. Liquid pharmaceutical composition
US11752208B2 (en) 2014-05-23 2023-09-12 Fresenius Kabi Deutschland Gmbh Liquid pharmaceutical composition
US10729769B2 (en) 2014-05-23 2020-08-04 Fresenius Kabi Deutschland Gmbh Liquid pharmaceutical composition
US10426832B2 (en) 2014-05-23 2019-10-01 Fresenius Kabi Deutschland Gmbh Liquid pharmaceutical composition
US10772961B2 (en) 2014-05-23 2020-09-15 Fresenius Kabi Deutschland Gmbh Liquid pharmaceutical composition
US10426833B2 (en) 2014-05-23 2019-10-01 Fresenius Kabi Deutschland Gmbh Liquid pharmaceutical composition
US11752209B2 (en) 2014-05-23 2023-09-12 Fresenius Kabi Deutschland Gmbh Liquid pharmaceutical composition
US11712471B2 (en) 2014-05-23 2023-08-01 Fresenius Kabi Deustschland GmbH Liquid pharmaceutical composition
US11707524B2 (en) 2014-05-23 2023-07-25 Fresenius Kabi Deutschland Gmbh Liquid pharmaceutical composition
AU2020286276B2 (en) * 2014-05-23 2023-06-01 Fresenius Kabi Deutschland Gmbh Liquid pharmaceutical composition
CN111939257A (en) * 2014-05-23 2020-11-17 费森尤斯卡比德国有限公司 Liquid pharmaceutical composition
EP3741358A1 (en) * 2014-05-23 2020-11-25 Fresenius Kabi Deutschland GmbH Liquid pharmaceutical composition
WO2015177059A1 (en) * 2014-05-23 2015-11-26 Ares Trading S.A. Liquid pharmaceutical composition
EP3939566A1 (en) * 2014-05-23 2022-01-19 Fresenius Kabi Deutschland GmbH Liquid pharmaceutical composition
US9926375B2 (en) 2014-11-12 2018-03-27 Tracon Pharmaceuticals, Inc. Anti-endoglin antibodies and uses thereof
US10155820B2 (en) 2014-11-12 2018-12-18 Tracon Pharmaceuticals, Inc. Anti-endoglin antibodies and uses thereof
US10336831B2 (en) 2014-11-12 2019-07-02 Tracon Pharmaceuticals, Inc. Use of anti-endoglin antibodies for treating ocular fibrosis
EP3053572A1 (en) * 2015-02-06 2016-08-10 Ares Trading S.A. Liquid pharmaceutical composition
WO2016124588A1 (en) * 2015-02-06 2016-08-11 Ares Trading S.A. Liquid pharmaceutical composition
EP3053573A1 (en) * 2015-02-06 2016-08-10 Ares Trading S.A. Liquid pharmaceutical composition
US10179811B2 (en) 2015-04-10 2019-01-15 Fresenius Kabi Deutschland Gmbh Methods of treating Crohn's disease or ulcerative colitis using an induction dosing regimen comprising anti-TNF-alpha antibody
US10689440B2 (en) 2015-04-10 2020-06-23 Fresenius Kabi Deutschland Gmbh Method of treating Crohn's disease and ulcerative colitis by using an induction dosing regimen of adalimumab
US10669333B2 (en) 2015-04-10 2020-06-02 Fresenius Kabi Deutschland Gmbh Method of treating a tumor necrosis factor α (TNFα)-related disorder by using an induction dosing regimen of adalimumab
US11229702B1 (en) 2015-10-28 2022-01-25 Coherus Biosciences, Inc. High concentration formulations of adalimumab
US11576971B2 (en) 2016-04-20 2023-02-14 Coherus Biosciences, Inc. Method of filling a container with no headspace
US11071782B2 (en) 2016-04-20 2021-07-27 Coherus Biosciences, Inc. Method of filling a container with no headspace
US11491223B2 (en) 2016-10-21 2022-11-08 Amgen Inc. Pharmaceutical formulations and methods of making the same
US10307483B2 (en) 2016-10-21 2019-06-04 Amgen Inc. Pharmaceutical formulations and methods of making the same
US11534403B2 (en) 2017-03-06 2022-12-27 Arecor Limited Liquid pharmaceutical composition
US11534402B2 (en) 2017-03-06 2022-12-27 Arecor Limited Liquid pharmaceutical composition
US10799597B2 (en) 2017-04-03 2020-10-13 Immunomedics, Inc. Subcutaneous administration of antibody-drug conjugates for cancer therapy
WO2018184693A1 (en) * 2017-04-07 2018-10-11 Ares Trading S.A. Liquid pharmaceutical composition
US11608357B2 (en) 2018-08-28 2023-03-21 Arecor Limited Stabilized antibody protein solutions
US11634485B2 (en) 2019-02-18 2023-04-25 Eli Lilly And Company Therapeutic antibody formulation

Also Published As

Publication number Publication date
IL166809A0 (en) 2006-01-15
CA2882905C (en) 2015-07-28
US20140314781A1 (en) 2014-10-23
US20150344563A1 (en) 2015-12-03
JP2014074034A (en) 2014-04-24
EP1528933A2 (en) 2005-05-11
PL212934B1 (en) 2012-12-31
HK1074008A1 (en) 2005-10-28
MY162068A (en) 2017-05-31
ZA200501032B (en) 2006-02-22
CA2882907A1 (en) 2004-02-26
KR20050067140A (en) 2005-06-30
CN102078608B (en) 2016-04-13
CA2882934C (en) 2015-07-28
US20190054171A1 (en) 2019-02-21
MY163027A (en) 2017-07-31
CY1118991T1 (en) 2018-01-10
JP2006511457A (en) 2006-04-06
EP2361637A1 (en) 2011-08-31
US20170056498A1 (en) 2017-03-02
US20210113694A1 (en) 2021-04-22
DK2359856T3 (en) 2017-07-17
JP2012046527A (en) 2012-03-08
SI1528933T1 (en) 2012-09-28
CA2882931A1 (en) 2004-02-26
PL218834B1 (en) 2015-01-30
KR101367743B1 (en) 2014-02-27
US9220781B2 (en) 2015-12-29
US20140086931A1 (en) 2014-03-27
EP2359856B1 (en) 2017-05-10
US20170151329A1 (en) 2017-06-01
US8802101B2 (en) 2014-08-12
CL2010000603A1 (en) 2010-11-12
ATE555809T1 (en) 2012-05-15
TW200500083A (en) 2005-01-01
US20220241415A1 (en) 2022-08-04
JP2015199741A (en) 2015-11-12
US9272042B2 (en) 2016-03-01
CA2494756C (en) 2014-07-22
US9114166B2 (en) 2015-08-25
US20180339046A1 (en) 2018-11-29
US20150306224A1 (en) 2015-10-29
SI2359856T1 (en) 2017-08-31
CA2882931C (en) 2016-08-09
US20140127222A1 (en) 2014-05-08
US9950066B2 (en) 2018-04-24
PL375272A1 (en) 2005-11-28
JP4925582B2 (en) 2012-04-25
PE20040994A1 (en) 2004-12-27
WO2004016286A2 (en) 2004-02-26
US20060153846A1 (en) 2006-07-13
US20140086929A1 (en) 2014-03-27
US20140322228A1 (en) 2014-10-30
KR20120130258A (en) 2012-11-29
US9295725B2 (en) 2016-03-29
US20150344560A1 (en) 2015-12-03
PL406852A1 (en) 2014-03-31
CN1688339A (en) 2005-10-26
ES2636692T3 (en) 2017-10-06
IL207028A0 (en) 2010-12-30
CA2872091A1 (en) 2004-02-26
US9327032B2 (en) 2016-05-03
CN102049045B (en) 2016-05-25
US9272041B2 (en) 2016-03-01
US20150093394A1 (en) 2015-04-02
US20150343065A1 (en) 2015-12-03
US8916157B2 (en) 2014-12-23
AU2003267744C1 (en) 2015-09-17
EP2363144A1 (en) 2011-09-07
US20150344562A1 (en) 2015-12-03
KR101529583B1 (en) 2015-06-18
JP2017165736A (en) 2017-09-21
US8216583B2 (en) 2012-07-10
CN101721702A (en) 2010-06-09
US20140086930A1 (en) 2014-03-27
UY27940A1 (en) 2004-03-31
EP2359856A1 (en) 2011-08-24
CA2872089C (en) 2015-07-14
US20170145087A1 (en) 2017-05-25
US8940305B2 (en) 2015-01-27
US8802102B2 (en) 2014-08-12
NZ538030A (en) 2006-10-27
MXPA05001841A (en) 2005-09-30
IL207028A (en) 2015-11-30
US9750808B2 (en) 2017-09-05
PL398596A1 (en) 2012-06-18
US9738714B2 (en) 2017-08-22
TWI331532B (en) 2010-10-11
CY1113353T1 (en) 2016-06-22
US20150344561A1 (en) 2015-12-03
US8916158B2 (en) 2014-12-23
KR20140092236A (en) 2014-07-23
US20120282270A1 (en) 2012-11-08
US8911741B2 (en) 2014-12-16
CA2872088A1 (en) 2004-02-26
MY153718A (en) 2015-03-13
AR077412A2 (en) 2011-08-24
CN101721702B (en) 2014-12-10
BR0313492A (en) 2005-07-05
EP1528933B1 (en) 2012-05-02
JP5608619B2 (en) 2014-10-15
US20140341924A1 (en) 2014-11-20
AR040881A1 (en) 2005-04-20
US8802100B2 (en) 2014-08-12
CA2882905A1 (en) 2004-02-26
US20160030578A1 (en) 2016-02-04
EP2363145A1 (en) 2011-09-07
US9302011B2 (en) 2016-04-05
DK1528933T3 (en) 2012-07-23
CA2494756A1 (en) 2004-02-26
PT1528933E (en) 2012-07-23
US8795670B2 (en) 2014-08-05
US20140341925A1 (en) 2014-11-20
US9289497B2 (en) 2016-03-22
KR101273568B1 (en) 2013-06-11
WO2004016286A3 (en) 2004-07-22
CN102078608A (en) 2011-06-01
CN102049045A (en) 2011-05-11
PT2359856T (en) 2017-06-23
ES2387616T3 (en) 2012-09-27
IL166809A (en) 2015-02-26
US20170158759A1 (en) 2017-06-08
CA2854798A1 (en) 2004-02-26
CN1688339B (en) 2012-05-09
KR20110036870A (en) 2011-04-11
US8932591B2 (en) 2015-01-13
AU2003267744A1 (en) 2004-03-03
CA2882907C (en) 2015-07-28
CA2882934A1 (en) 2004-02-26
CA2872089A1 (en) 2004-02-26
US9732152B2 (en) 2017-08-15
PL218221B1 (en) 2014-10-31

Similar Documents

Publication Publication Date Title
US9732152B2 (en) Formulation of human antibodies for treating TNF-alpha associated disorders

Legal Events

Date Code Title Description
AS Assignment

Owner name: ABBOTT BIOTECHNOLOGY LTD., BERMUDA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:KRAUSE, HANS-JUERGEN;BAUST, LISA;DICKES, MICHAEL;REEL/FRAME:014389/0458

Effective date: 20021212

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: ABBVIE BIOTECHNOLOGY LTD., BERMUDA

Free format text: CHANGE OF NAME;ASSIGNOR:ABBOTT BIOTECHNOLOGY LTD.;REEL/FRAME:031217/0148

Effective date: 20120625