US20050244371A1 - Method and system to remove cytokine inhibitor in patients - Google Patents

Method and system to remove cytokine inhibitor in patients Download PDF

Info

Publication number
US20050244371A1
US20050244371A1 US11/153,524 US15352405A US2005244371A1 US 20050244371 A1 US20050244371 A1 US 20050244371A1 US 15352405 A US15352405 A US 15352405A US 2005244371 A1 US2005244371 A1 US 2005244371A1
Authority
US
United States
Prior art keywords
patient
treatment
antibodies
soluble
tnf
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
US11/153,524
Inventor
M. Lentz
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.)
INNATUS Corp
Original Assignee
Biopheresis Technologies Inc
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=46177762&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20050244371(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from US09/083,307 external-priority patent/US6620382B1/en
Application filed by Biopheresis Technologies Inc filed Critical Biopheresis Technologies Inc
Priority to US11/153,524 priority Critical patent/US20050244371A1/en
Publication of US20050244371A1 publication Critical patent/US20050244371A1/en
Assigned to BIOPHERESIS TECHNOLOGIES, LLC reassignment BIOPHERESIS TECHNOLOGIES, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LENTZ, M. RIGDON
Assigned to BIOPHERESIS TECHNOLOGIES, INC. reassignment BIOPHERESIS TECHNOLOGIES, INC. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: BIOPHERESIS TECHNOLOGIES, LLC
Assigned to INNATUS CORPORATION reassignment INNATUS CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BIOPHERESIS TECHNOLOGIES, INC.
Abandoned legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/555Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/10Inactivation or decontamination of a medicinal preparation prior to administration to an animal or a person
    • A61K41/17Inactivation or decontamination of a medicinal preparation prior to administration to an animal or a person by ultraviolet [UV] or infrared [IR] light, X-rays or gamma rays
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/342Adding solutions to the blood, e.g. substitution solutions
    • A61M1/3455Substitution fluids
    • A61M1/3468Substitution fluids using treated filtrate as substitution fluid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/3472Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/3472Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
    • A61M1/3482Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate by filtrating the filtrate using another cross-flow filter, e.g. a membrane filter
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/3496Plasmapheresis; Leucopheresis; Lymphopheresis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/04Immunostimulants
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/505Medicinal preparations containing antigens or antibodies comprising antibodies
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/342Adding solutions to the blood, e.g. substitution solutions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/342Adding solutions to the blood, e.g. substitution solutions
    • A61M1/3441Substitution rate control as a function of the ultrafiltration rate
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/3472Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
    • A61M1/3486Biological, chemical treatment, e.g. chemical precipitation; treatment by absorbents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00Special media to be introduced, removed or treated
    • A61M2202/04Liquids
    • A61M2202/0413Blood
    • A61M2202/0415Plasma
    • A61M2202/0417Immunoglobulin
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/70Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention is generally in the field of enhancing an immune response, and particularly relates to the removal of TNF inhibitors in a patient, such as a cancer patient, to promote inflammation and thereby induce remission of the cancer.
  • GM-CSF granulocyte macrophage colony stimulating factor
  • G-CSF erythropoietin
  • M-CSF macrophage colony stimulating factor
  • SCF stem cell factor
  • Vaccines to stimulate the patient's immune system have been attempted, but not with great success.
  • Various cytokines, alone or in combination, such as tumor necrosis factor, interferon gamma, and interleukin-2 (“IL-2”) have been used to kill cancers, but have not produced cures.
  • anti-angiogenic compounds such as thalidomide have been tried in compassionate use cases and shown to cause tumor remission.
  • compounds inducing a procoagulant state such as an inhibitor of protein C, have been used to cause tumor remission.
  • TNF-Rs tumor necrosis factor receptors
  • U.S. Pat. No. 4,708,713 to Lentz describes an alternative method for treating cancer, involving ultrapheresis to remove compounds based on molecular weight, which promotes an immune attack on the tumors by the patient's own white cells.
  • a method to treat disorders characterized by production of soluble TNF receptors, such as many types of cancer, and certain diseases such as HIV, where the disease immunosuppresses the patient, has been developed.
  • Antibodies which bind to TNF receptor, including the soluble TNF receptor, are administered to the patient in an amount effective to neutralize the molecules which block binding of TNF to the receptor, thereby inducing inflammation.
  • the patient's blood is passed through a column having antibodies immobilized thereon, which bind to and remove the soluble TNF receptor molecules.
  • the process can be performed alone or in combination with other therapies, including radiation, chemotherapy (local or systemic, for example, treatments using alkylating agents, doxyrubicin, carboplatinum, cisplatinum, and taxol, and other drugs which may be synergistic in effect with “unblocked” cytokines: or anti-angiogenic factors.
  • Antibodies may be utilized which are immunoreactive with one or more of the following:
  • tissue necrosis factor receptor-1 (“TNFR-1”), tissue necrosis factor receptor-2 (“TNFR-2”), interleukin-2 receptor (“IL-2R”), interleukin-1 receptor (“IL-1R”), interleukin-6 receptor (“IL-6R”), or interferon-gamma receptor (“sIFN-gammaR”).
  • TNFR-1 tissue necrosis factor receptor-1
  • TNFR-2 tissue necrosis factor receptor-2
  • IL-2R interleukin-2 receptor
  • IL-1R interleukin-1 receptor
  • IL-6R interleukin-6 receptor
  • IFN-gammaR interferon-gamma receptor
  • TNF- tumor necrosis factor
  • a related cytokine produced and secreted by killer T-lymphocytes with highly selective antigen specific receptors Old L. J., Antitumor activity of microbial products and tumor necrosis factor, and Bonavida B, et al., (eds): Tumor Necrosis Factor/Cachecin and Related Cytokines, Basell, Karger, 1988.
  • TNF tumor necrosis factor
  • Haranaka K., et al Cytotoxic activity of tumor necrosis factor (TNF) on human cancer cells in vitro, Jpn J Exp Med 1981; 51:191; Urban J. L. II, et al., Tumor necrosis factor: A potent effector molecule for tumor cell killing by activated macrophages, Proc Natl Acad Sce USA 1986; 83-5233; Philip R., et al., Tumor necrosis factor as immunomodulator and mediator of monocyte cytotoxicity induced by itself, Gamma-interferon and Interleukin-1 , Nature 1986; 323:86; Ziegler-Heitbrock H.
  • Tumor necrosis factor as effector molecule in monocyte-mediated cytotoxicity, Cancer Res 1986; 46:5947; and Feinman R., et al., Tumor necrosis factor is a important mediator of tumor cell killing by human monocytes, J Immunol 1987; 138:635. They derive from billions of clones, each with its own specificity. Thus, one clone of these thymus derived lymphocytes gives rise to T-killer (cytotoxic lymphocytes), or other functional classes each with the one specificity of the parent clone. Their mechanisms are related to both antibody dependent and antibody independent cellular tumor toxicity.
  • Receptors for TNF on neoplastic, viral infected, aged cells or those otherwise targeted for destruction can be both a curse and a curse. In a positive role, they allow binding of TNF to the surface for internalization and destruction of the cell. Unfortunately this receptor hypothesis has a double edge.
  • Certain neoplastic cells such as active melanomas secrete large amounts of these receptors (sTNF-R1 and sTNF-R2) that promptly bind TNF before it can get within the vicinity of the cell, Haranaka K., et al, Cytotoxic activity of tumor necrosis factor (TNF) on human cancer cells in vitro, Jpn J Exp Med 1981; 51:191; Urban J. L.
  • Tumor necrosis factor A potent effector molecule for tumor cell killing by activated macrophages, Proc Natl Acad Sce USA 1986; 83-5233; Philip R., et al., Tumor necrosis factor as immunomodulator and mediator of monocyte cytotoxicity induced by itself, Gamma-interferon and Interleukin-1 , Nature 1986; 323:86; Ziegler-Heitbrock H.
  • Tumor necrosis factor as effector molecule in monocyte-mediated cytotoxicity, Cancer Res 1986; 46:5947; and Feinman R., et al., Tumor necrosis factor is a important mediator of tumor cell killing by human monocytes, J Immunol 1987; 138:635. This serves as a defense mechanism on the part of the targeted cell rendering the host immune system ineffective.
  • TNF-R1 and R2 have been characterized with respect to molecular weights (55 and 75 kD respectively), Old L.
  • TNF and LT differ in their receptor binding properties and the induction of MHC class I proteins on a human CD4+ T cell hybridoma, J Immunol 1990; 144:2582-2591. They serve to both down regulate the immune response in a normal fashion and overly suppress the immune response as stated above with respect to certain malignancies. They are particularly abundant, and at high level, in patients with melanoma.
  • soluble cytokine receptors which function as inhibitors of the cytokine
  • the neutralizing agent is typically an antibody reactive with the receptor.
  • the antibodies will typically be reactive with both the soluble and immobilized forms of the receptor.
  • soluble tumor necrosis factor receptor (“sRNF-R”), soluble interleukin-2 receptor (“sIL-2R”), soluble interleukin-1 receptor (“sIL-1R”), soluble interleukin-6 receptor (“sIL-6R”), or soluble interferon-gamma receptor (“sIFN-gammaR”).
  • the receptors can be removed by binding to the cytokine, an epitope thereof, or an antibody to the receptor.
  • the antibodies to the receptors can be immobilized in a filter, in a column, or using other standard techniques for binding reactions to remove proteins from the blood or plasma of a patient, or administered directly to the patient in a suitable pharmaceutically acceptable carrier such as saline.
  • antibody refers to antibody, or antibody fragments (single chain, recombinant, or humanized), immunoreactive against the receptor molecules.
  • the antibody is reactive with the carboxy-terminus of the shed receptor molecules, thereby avoid concerns with signal transduction by the receptor is still present on the cell surface.
  • Antibodies can be obtained from various commercial sources such as Genzyme Pharmaceuticals. These are preferably humanized for direct administration to a human, but may be of animal origin if immobilized in an extracorporeal device. Antibodies may be monoclonal or polyclonal. The antibodies and device should be sterilized and treated to remove endotoxin and other materials not acceptable for administration to a patient.
  • Antibodies to the receptor proteins can be generated by standard techniques, using human receptor proteins. Antibodies are typically generated by immunization of an animal using an adjuvant such as Freund's adjuvant in combination with an immunogenic amount of the protein administered over a period of weeks in two to three week intervals, then isolated from the serum, or used to make hybridomas which express the antibodies in culture. Because the methods for immunizing animals yield antibody which is not of human origin, the antibodies could elicit an adverse effect if administered to humans. Methods for “humanizing” antibodies, or generating less immunogenic fragments of non-human antibodies, are well known.
  • a humanized antibody is one in which only the antigen-recognized sites, or complementarily-determining hypervariable regions (CDRs) are of non-human origin, whereas all framework regions (FR) of variable domains are products of human genes. These “humanized” antibodies present a lesser xenographic rejection stimulus when introduced to a human recipient.
  • variable region DNA of a selected animal recombinant anti-idiotypic ScFv is sequenced by the method of Clackson, T., et al., (1991) Nature, 352:624-688, incorporated herein by reference.
  • animal CDRs are distinguished from animal framework regions (FR) based on locations of the CDRs in known sequences of animal variable genes. Kabat, H.
  • the CDRs are grafted onto human heavy chain variable region framework by the use of synthetic oligonucleotides and polymerase chain reaction (PCR) recombination. Codons for the animal heavy chain CDRs, as well as the available human heavy chain variable region framework, are built in four (each 100 bases long) oligonucleotides. Using PCR, a grated DNA sequence of 400 bases is formed that encodes for the recombinant animal CDR/human heavy chain FR protection.
  • PCR polymerase chain reaction
  • the immunogenic stimulus presented by the monoclonal antibodies so produced may be further decreased by the use of Pharmacia's (Pharmacia LKB Biotechnology, Sweden) “Recombinant Phage Antibody System” (RPAS), which generated a single-chain Fv fragment (ScFv) which incorporates the complete antigen-binding domain of the antibody.
  • RPAS Recombinant Phage Antibody System
  • ScFv Single-chain Fv fragment
  • antibody variable heavy and light chain genes are separately amplified from the hybridoma mRNA and cloned into an expression vector.
  • the heavy and light chain domains are co-expressed on the same polypeptide chain after joining with a short linker DNA which codes for a flexible peptide.
  • This assembly generated a single-chain Fv fragment (ScFv) which incorporates the complete antigen-binding domain of the antibody.
  • the recombinant ScFv includes a considerably lower number of epitopes, and thereby presents a much weaker immunogenic stimulus when
  • the antibodies can be formulated in standard pharmaceutical carriers for administration to patients in need thereof. These include saline, phosphate buffered saline, and other aqueous carriers, and liposomes, polymeric microspheres and other controlled release deliver devices, as are well known in the art.
  • the antibodies can also be administered with adjuvant, such as muramyl dipeptide or other materials approved for use in humans (Freund's adjuvant can be used for administration of antibody to animals).
  • adjuvant such as muramyl dipeptide or other materials approved for use in humans (Freund's adjuvant can be used for administration of antibody to animals).
  • antibodies are immobilized to a solid support, such as the SEPHAROSETM column in the examples, using standard techniques such as cyanogen bromide or commercially available kits for coupling of proteins to membranes formed of materials such as nitrocellulose or polycarbonate.
  • Treatment is conducted over a period of time until a positive indication is observed. This is typically based on diagnostic tests which show that there has been some reduction in tumor size or which suggests tumor inflammation.
  • the patient is preferably treated daily for three weeks, diagnostic tests conducted to verity that there has been shrinkage of the tumors and/or inflammation, then the treatment regime is repeated.
  • Surgical (or vacuum) removal of necrotic material may be required prior to or during treatment to avoid toxicity associated with high tumor burden.
  • anti-angiogenic compound Any anti-angiogenic compound can be used.
  • exemplary anti-angiogenic compounds include O-substituted fumagillol and derivatives thereof, such as TNP-470, described in U.S. Pat. Nos. 5,135,919, 5,698,586, and 5,290,807 to Kishimoto, et al.; angiostatin and endostatin, described in U.S. Pat. No. 5,290,807, 5,639,725 and 5,733,876 to O'Reilly; thalidomide, as described in U.S. Pat. Nos.
  • Protein C is a vitamin K-dependent plasma protein zymogen to a serine protease. Upon activation it becomes a potent anticoagulant. Activated protein C acts through the specific proteolysis of the procoagulant cofactors, factor VIIIa and factor Va. This activity requires the presence of another vitamin K-dependent protein, protein S, calcium and a phospholipid (presumably cellular) surface. As described in Hemostasis and Thrombosis: Basic Principles and Clinical Practice 2nd Ed., Colman, R. W., et al., p. 263 (J. B. Lippincott, Philadelphia, Pa. 1987), protein C circulates in a two-chain form, with the larger, heavy chain bound to the smaller light chain through a single disulfide link.
  • Protein C is activated to activated protein C (APC).
  • APC activated protein C
  • Thrombin is capable of activating protein C by the specific cleavage of the Arg 12 -Leu 13 bond in the heavy chain.
  • the rate of this activation is enhanced dramatically when thrombin is bound to the endothelial cell cofactor, thrombomodulin.
  • Matschiner, et al., Current Advances in Vitamin K Research , pp. 135-140, John W. Suttie, ed. (Elsevier Science Publishing Co., Inc. 1988) have further reviewed the role of the Vitamin K dependent proteins in coagulation.
  • Blockage of the natural anticoagulant pathways uses the natural procoagulant properties of the tumor to target the tumor capillaries for microvascular thrombosis, leading to hemorrhagic necrosis of the tumor, as described in U.S. Pat. No. 5,147,638 to Esmon, et al.
  • examples of such compounds include anti-protein C and anti-protein S.
  • TNF alpha and TNF beta in doses of between approximately 100 to 500 micrograms per meter squared body surface area (M2BSA), can enhance the immune reaction in aggressive tumors.
  • Monocyte and lymphocyte activation is augmented by INF-alpha, INF-beta and gamma.
  • the IL-1 and IL-2 receptor antagonists are removed by ultrapheresis and thereby upregulate the in vivo activity of these cytokines.
  • IFN-alpha and beta are 3 M units subcutaneous three times a week up to 20 M units/M2 BSA daily.
  • Interferon-gamma is administered in a dosage of between 100 to 1000 micgms per day.
  • Preferred chemotherapeutic agents are those which are synergistic with TNF, for example, alkylating agents, doxyrubicin, carboplatinum, cisplatinum, and tomoxifen.
  • Tamoxifen plays a role not only in blocking of estrogen receptors but also certain growth factor receptors such as epidermal derived growth factor (“EDGF”), fibroblast derived growth factor (“FDGF”), tumor derived growth factor (“TDGF”), TDGF- ⁇ and platelet derived growth factor (“PDGF”) and therefore may be complementary to inflammation against cancers provoked by ultrapheresis.
  • EDGF epidermal derived growth factor
  • FDGF fibroblast derived growth factor
  • TDGF tumor derived growth factor
  • PDGF- ⁇ platelet derived growth factor
  • Ultrapheresis allows the use of lower doses of radiation to kill residual tumor cells and spare normal tissue.
  • ultrapheresis is used as the initial therapy, followed by radiation at approximately one-half of the normal dosages. It is well established that TNF kills tumor cells by generating free oxygen radicals, hydroxyl radicals and halide ions, and that radiation therapy generates carbonium ions in tissue. Therefore the combination of the two is more effective in killing cancer cells than either alone.
  • Monoclonal antibody was obtained from R&D Systems, Minneapolis, Minn., and purified for administration to a patient. This antibody is reactive with TNF R1 and R2 inhibitors.
  • a filtration system was assembled using an Eva Flux 4 A filter as the primary filter to remove ultrafiltrate containing these inhibitors from the cancer patient's blood.
  • Monoclonal antibody in a dose of 1 mg per liter of normal ultrafiltrate of the monoclonal antibody and 1 mg of the $2 monoclonal antibody were added to that replacement solution.
  • the ultrafiltrate of the initial 4 A filter was delivered by a separate blood pump to a Kuraray 3 A filter.
  • the retentate of the 3A filter was then discarded and the ultrafiltrate of the 3A filter was metered back into the filtered blood from the 4 A filter as replacement solution.
  • normal ultrafiltrate with monoclonal antibody added to it was metered into the intra circuit between the 4 A and 3 A filters.
  • this murine monoclonal antibody could capture the inhibitor and aid in its removal from blood since the complex of antibody and antigen could not pass through the pores of the 3 A filter and thus be discarded in the retentate of the 3A filter. This was considerably more effective than the single separation technique and replacement with normal ultrafiltrate. There was also a heightened tumor specific inflammatory response by doing this and an increased rate of tumor destruction.
  • the monoclonal antibody preferably humanized to 97% to 99% human form by substituting human constant regions for human constant regions on the antibody, preserve its capturing and neutralizing capability with the murine variable regions of the antibody and use the antibody as the therapeutic drug in clinical trials with a very high expectation that it would neutralize soluble receptors to TNF and cause tumor destruction in a human.
  • a patient with vaginal metastasis of colon cancer was treated for one week with a three hour infusion of monoclonal antibody to TNF receptor 1 and TNF receptor 2. This led to a 75% reduction in the tumor size within one week.
  • a procedure is described in case report form, that utilizes apheresis and immunological affinity chromatography to treat a melanoma patient with short term need and weakening long term prognosis.
  • the patient is a 55 year old Russian woman with metastatic melanoma.
  • the patient smoked 2-3 packs of cigarettes a day for some 20 years. He quit this habit several years ago. He was also a heavy alcohol user in years past but had decreased his intake to 1-2 glasses of wine a day. Review of his medications on this date revealed methylprednisolone 4 mg in AM and 4 mg in PM. Apparently this was being taken as replacement therapy for adrenal cortical suppression that was graded iatrogenically at the time of the treatment of his alveolitis (see below). He was additionally taking narcotic analgesics. As a child he suffered the usual childhood diseases, denies rheumatic fever, scarlet fever or diphtheria. As an adult he has had no major medical illnesses save those described above. He has had no other major surgeries in the past and has no known allergies.
  • one lymph node was histologically confirmed to involve melanoma.
  • the patient was treated with a course of Vindesine 3 mg/m 2 every three weeks, dacarbazine 100 mg/m 2 every three weeks for four cycles. He subsequently developed cutaneous metastases in the skin of his left shoulder, multiple metastases to the scars within the left anterolateral neck and multiple axillary metastases treated with fifteen subsequent excisions of recurrent metastases.
  • March of 1999 he was offered a trial of Interleukin-2 but on this developed severe pulmonary toxicity that had a protracted course and was diagnosed as idiopathic fibrosing alveolitis.
  • Interleukin-2 was discontinued and he received radiation therapy to his right neck and axilla for six weeks beginning in the month of May 1999. He developed low back pain in August of 1999. Work up in October of 1999 revealed bone metastasis of the vertebral body of T-11 and subsequent MRI revealed a lytic destructive process in the right transverse process and pedicle of the 11 th thoracic vertebra, as well as complete replacement of the vertebral body at T-11. Additional metastases were appreciated in the vertebral body of the 9 th thoracic vertebral as well as the 10th. Also there was involvement of L-1 and L-2 vertebral bodies. Tumor seen again on the Mar.
  • His cerebellar examination revealed no dysmetria, dysarthria or dysdiadochokinesia. He was essentially confined to bed due to back pain only, but was able to roll from left to right without assistance. He had been confined to a wheelchair for the antecedent two months due to back pain and was wearing a back brace which was removed for physical exam.
  • the material eluted from the column was then analyzed for the level of each inhibitor still in the plasma and 50 cc's of that plasma was then injected into the patient at the end of pheresis to look for any febrile reactions or allergic reactions. He tolerated this with no apparent clinical adverse effect.
  • His R1 level before treatment was 1500 and after treatment was 1450.
  • His R2 level before treatment was 5000 and after treatment was 3800 on this date. Again he tolerated the procedure well with no clinical adverse effect and no increase in pain in his back.
  • the patient remains active, with good appetite, is walking normally and his back pain is much improved. He has positive anticipation for his second course of apheretic treatments.
  • Polyclonal antibodies were produced in New Zealand white rabbits injected with recombinant antigen, soluble tumor necrosis factor receptor (“STNF”) R1 and R, injected into the rabbit on a standard immunization protocol, then boosted. 200 mg of polyclonal antibody may be produced against STNF R1 and R2, per liter. The animals will be bled monthly. 200 mg of antibody can be bound safely to 200 mg of AH SEPHAROSETM beads. The binding is done with ethanolamine and periodate. Binding is therefore excellent. This matrix is then placed in a 200 mg polycarbonate column. Each step is done in an aseptic fashion and the final product is then terminally sterilized with standard radiation protocols and subjected to USDA standard testing for pyrogen and infectious agents.
  • STNF soluble tumor necrosis factor receptor
  • This amount of antibody is enough to remove STNF R1 and STNF R2 in human extracellular water sufficient to reduce the level of 10,000 pg per ml to under 1,000 pg per ml in two to three hours of plasma exchange.
  • the treatment is expected to produce excellent responses in these tumor types and may play a role in the clinical management of hematopoietic disorders as well.
  • the methods and systems disclosed herein are useful for treatment of patients with cancer, immune-mediated disorders, chronic parasitism, some viral diseases especially viral diseases such as HIV which cause immunosuppresion, and other disorders characterized by elevated levels of TNF receptors or inhibitors to IL-2, IL-6, gamma interferon, or other pro-inflammatory signals as well as white cell activation.
  • An example demonstrates efficacy in treating a cancer patient.

Abstract

A method to treat cancer uses ultrapheresis, refined to remove compounds of less than 120,000 daltons molecular weight, followed by administration of replacement fluid, to stimulate the patient's immune system to attack solid tumors. In the preferred embodiment, the patient is ultrapheresed using a capillary tube ultrafilter having a pore size of 0.02 to 0.05 microns, with a molecular weight cutoff of 120,000 daltons, sufficient to filter one blood volume. The preferred replacement fluid is ultrapheresed normal plasma. The patient is preferably treated daily for three weeks, diagnostic tests conducted to verify that there has been shrinkage of the tumors, then the treatment regime is repeated. The treatment is preferably combined with an alternative therapy, for example, treatment with an anti-angiogenic compound, one or more cytokines such as TNF, gamma interferon, or IL-2, or a procoagulant compound. The treatment increases endogenous, local levels of cytokines, such as TNF. This provides a basis for an improved effect when combined with any treatment that enhances cytokine activity against the tumors, for example, treatments using alkylating agents, doxyrubicin, carboplatinum, cisplatinum, and taxol. Alternatively, the ultrapheresis treatment can be combined with local chemotherapy, systemic chemotherapy, and/or radiation.

Description

    BACKGROUND OF THE INVENTION
  • The present invention is generally in the field of enhancing an immune response, and particularly relates to the removal of TNF inhibitors in a patient, such as a cancer patient, to promote inflammation and thereby induce remission of the cancer.
  • This application claims priority to U.S. Ser. No. 60/164,695, filed Nov. 10, 1999.
  • Conventional cancer therapy is based on the use of drugs and/or radiation which kills replicating cells, hopefully faster than the agents kill the patient's normal cells. Surgery is used to reduce tumor bulk, but has little impact once the cancer has metastasized. Radiation is effective only in a localized area.
  • The treatments can in themselves kill the patient, in the absence of maintenance therapy. For example, for some types of cancer, bone marrow transplants have been used to maintain the patient following treatment with otherwise fatal amounts of chemotherapy. Efficacy has not been proven for treatment of solid tumors, however. “Cocktails” of different chemotherapeutic agents and combinations of very high doses of chemotherapy with restorative agents, for example, granulocyte macrophage colony stimulating factor (“GM-CSF”), erythropoietin, thrombopoetin granulocyte stimulating factor, (“G-CSF”), macrophage colony stimulating factor (“M-CSF”) and stem cell factor (“SCF”) to restore platelet and white cell levels, have been used to treat aggressive cancers. Even with the supportive or restrictive therapy, side effects are severe.
  • Other treatments have been tried in an attempt to improve mortality and morbidity. Vaccines to stimulate the patient's immune system have been attempted, but not with great success. Various cytokines, alone or in combination, such as tumor necrosis factor, interferon gamma, and interleukin-2 (“IL-2”) have been used to kill cancers, but have not produced cures. More recently, anti-angiogenic compounds such as thalidomide have been tried in compassionate use cases and shown to cause tumor remission. In animal studies, compounds inducing a procoagulant state, such as an inhibitor of protein C, have been used to cause tumor remission. New studies have shown that soluble cytokine receptors, such as tumor necrosis factor receptors (“TNF-Rs”) which are released in a soluble form from tumor cells, in high concentrations relative to normal cells, may restore the immune system's attack on the tumor cells (Jablonska and Peitruska, Arch. Immunol. Ther. Exp. (Warsz) 1997, 45(5-6), 449-453; Chen, et al., J. Neuropathol. Exp. Neurol. 1997, 56(5), 541-550).
  • U.S. Pat. No. 4,708,713 to Lentz describes an alternative method for treating cancer, involving ultrapheresis to remove compounds based on molecular weight, which promotes an immune attack on the tumors by the patient's own white cells.
  • Despite all of these efforts, many patients die from cancer; others are terribly mutilated. It is unlikely that any one therapy will be effective to cure all types of cancer.
  • It is therefore an object of the present invention to provide a method and system for treatment of solid tumors.
  • It is a further object of the present invention to provide a method and compositions that does not involve non-selective, extremely toxic, systemic chemotherapy.
  • SUMMARY OF THE INVENTION
  • A method to treat disorders characterized by production of soluble TNF receptors, such as many types of cancer, and certain diseases such as HIV, where the disease immunosuppresses the patient, has been developed. Antibodies which bind to TNF receptor, including the soluble TNF receptor, are administered to the patient in an amount effective to neutralize the molecules which block binding of TNF to the receptor, thereby inducing inflammation. In the preferred embodiment, the patient's blood is passed through a column having antibodies immobilized thereon, which bind to and remove the soluble TNF receptor molecules. The process can be performed alone or in combination with other therapies, including radiation, chemotherapy (local or systemic, for example, treatments using alkylating agents, doxyrubicin, carboplatinum, cisplatinum, and taxol, and other drugs which may be synergistic in effect with “unblocked” cytokines: or anti-angiogenic factors. Antibodies may be utilized which are immunoreactive with one or more of the following:
  • tissue necrosis factor receptor-1 (“TNFR-1”), tissue necrosis factor receptor-2 (“TNFR-2”), interleukin-2 receptor (“IL-2R”), interleukin-1 receptor (“IL-1R”), interleukin-6 receptor (“IL-6R”), or interferon-gamma receptor (“sIFN-gammaR”). The patient is preferably treated daily for at least three weeks, diagnostic tests conducted to verify that there has been shrinkage of the tumors, then the treatment regime is repeated as needed.
  • DETAILED DESCRIPTION OF THE INVENTION
  • Innate, natural and antigen specific killer mechanisms represent the best arsenal for dealing with melanoma cells in vitro and in vivo. Central to these cellular destructive mechanisms is tumor necrosis factor (TNF-), an inflammatory cytokine produced by macrophages and earlier mononuclear cells and TNF-, a related cytokine produced and secreted by killer T-lymphocytes with highly selective antigen specific receptors, Old L. J., Antitumor activity of microbial products and tumor necrosis factor, and Bonavida B, et al., (eds): Tumor Necrosis Factor/Cachecin and Related Cytokines, Basell, Karger, 1988. p7; Haranaka K., et al, Cytotoxic activity of tumor necrosis factor (TNF) on human cancer cells in vitro, Jpn J Exp Med 1981; 51:191; Urban J. L. II, et al., Tumor necrosis factor: A potent effector molecule for tumor cell killing by activated macrophages, Proc Natl Acad Sce USA 1986; 83-5233; Philip R., et al., Tumor necrosis factor as immunomodulator and mediator of monocyte cytotoxicity induced by itself, Gamma-interferon and Interleukin-1, Nature 1986; 323:86; Ziegler-Heitbrock H. W., et al., Tumor necrosis factor as effector molecule in monocyte-mediated cytotoxicity, Cancer Res 1986; 46:5947; and Feinman R., et al., Tumor necrosis factor is a important mediator of tumor cell killing by human monocytes, J Immunol 1987; 138:635. They derive from billions of clones, each with its own specificity. Thus, one clone of these thymus derived lymphocytes gives rise to T-killer (cytotoxic lymphocytes), or other functional classes each with the one specificity of the parent clone. Their mechanisms are related to both antibody dependent and antibody independent cellular tumor toxicity. Receptors for TNF on neoplastic, viral infected, aged cells or those otherwise targeted for destruction can be both a blessing and a curse. In a positive role, they allow binding of TNF to the surface for internalization and destruction of the cell. Unfortunately this receptor hypothesis has a double edge. Certain neoplastic cells such as active melanomas secrete large amounts of these receptors (sTNF-R1 and sTNF-R2) that promptly bind TNF before it can get within the vicinity of the cell, Haranaka K., et al, Cytotoxic activity of tumor necrosis factor (TNF) on human cancer cells in vitro, Jpn J Exp Med 1981; 51:191; Urban J. L. II, et al., Tumor necrosis factor: A potent effector molecule for tumor cell killing by activated macrophages, Proc Natl Acad Sce USA 1986; 83-5233; Philip R., et al., Tumor necrosis factor as immunomodulator and mediator of monocyte cytotoxicity induced by itself, Gamma-interferon and Interleukin-1, Nature 1986; 323:86; Ziegler-Heitbrock H. W., et al., Tumor necrosis factor as effector molecule in monocyte-mediated cytotoxicity, Cancer Res 1986; 46:5947; and Feinman R., et al., Tumor necrosis factor is a important mediator of tumor cell killing by human monocytes, J Immunol 1987; 138:635. This serves as a defense mechanism on the part of the targeted cell rendering the host immune system ineffective. TNF-R1 and R2 have been characterized with respect to molecular weights (55 and 75 kD respectively), Old L. J., Antitumor activity of microbial products and tumor necrosis factor, and Bonavida B, et al., (eds): Tumor Necrosis Factor/Cachecin and Related Cytokines, Basell, Karger, 1988. p7, Langkopf F., et al., Soluble tumor necrosis factor receptors as prognostic factors in cancer patients, Lancet 1994; 344:57-58; Howard S. T., et al., Vaccinia virus homologues of the Shope fibroma virus inverted terminal repeat proteins and a discontinuous ORF related to the tumor necrosis factor receptor family, Virology 1991; 180:633-664; Mathias S, et al., Activation of the Sphingomyelin signaling pathway intact EL4 cells and in a cell-free system by IL-1b, Science 1993; 259-519-522; and Andrews J. S., et al., Characterization of the receptor for tumor necrosis factor (TNF) and lymphotoxin LT) on human T lymphocytes: TNF and LT differ in their receptor binding properties and the induction of MHC class I proteins on a human CD4+ T cell hybridoma, J Immunol 1990; 144:2582-2591. They serve to both down regulate the immune response in a normal fashion and overly suppress the immune response as stated above with respect to certain malignancies. They are particularly abundant, and at high level, in patients with melanoma.
  • I. Anti-Cytokine Receptor Molecules.
  • Selective removal or neutralization of the soluble cytokine receptors (which function as inhibitors of the cytokine) can be used to promote a selective, safe inflammatory response against a tumor or cells infected with a pathogen such as a virus like HIV or parasite. The neutralizing agent is typically an antibody reactive with the receptor. the antibodies will typically be reactive with both the soluble and immobilized forms of the receptor. These include soluble tumor necrosis factor receptor (“sRNF-R”), soluble interleukin-2 receptor (“sIL-2R”), soluble interleukin-1 receptor (“sIL-1R”), soluble interleukin-6 receptor (“sIL-6R”), or soluble interferon-gamma receptor (“sIFN-gammaR”). The advantage of selective removal or neutralization is that the same beneficial effect is obtained in treatment of the disorder but the treatment is much less expensive and safer since exogenous plasma or albumin does not have to be administered to the patient when there is selective removal, as in the case of ultrapheresis and the cytotoxic effects of radiation and chemotherapy are avoided.
  • The receptors can be removed by binding to the cytokine, an epitope thereof, or an antibody to the receptor. The antibodies to the receptors can be immobilized in a filter, in a column, or using other standard techniques for binding reactions to remove proteins from the blood or plasma of a patient, or administered directly to the patient in a suitable pharmaceutically acceptable carrier such as saline. As used herein, antibody refers to antibody, or antibody fragments (single chain, recombinant, or humanized), immunoreactive against the receptor molecules. In the most preferred embodiment, the antibody is reactive with the carboxy-terminus of the shed receptor molecules, thereby avoid concerns with signal transduction by the receptor is still present on the cell surface.
  • Antibodies can be obtained from various commercial sources such as Genzyme Pharmaceuticals. These are preferably humanized for direct administration to a human, but may be of animal origin if immobilized in an extracorporeal device. Antibodies may be monoclonal or polyclonal. The antibodies and device should be sterilized and treated to remove endotoxin and other materials not acceptable for administration to a patient.
  • Antibodies to the receptor proteins can be generated by standard techniques, using human receptor proteins. Antibodies are typically generated by immunization of an animal using an adjuvant such as Freund's adjuvant in combination with an immunogenic amount of the protein administered over a period of weeks in two to three week intervals, then isolated from the serum, or used to make hybridomas which express the antibodies in culture. Because the methods for immunizing animals yield antibody which is not of human origin, the antibodies could elicit an adverse effect if administered to humans. Methods for “humanizing” antibodies, or generating less immunogenic fragments of non-human antibodies, are well known. A humanized antibody is one in which only the antigen-recognized sites, or complementarily-determining hypervariable regions (CDRs) are of non-human origin, whereas all framework regions (FR) of variable domains are products of human genes. These “humanized” antibodies present a lesser xenographic rejection stimulus when introduced to a human recipient.
  • To accomplish humanization of a selected mouse monoclonal antibody, the CDR grafting method described by Daugherty, et al., (1991) Nucl. Acids Res., 19:2471-2476, incorporated herein by reference, may be used. Briefly, the variable region DNA of a selected animal recombinant anti-idiotypic ScFv is sequenced by the method of Clackson, T., et al., (1991) Nature, 352:624-688, incorporated herein by reference. Using this sequence, animal CDRs are distinguished from animal framework regions (FR) based on locations of the CDRs in known sequences of animal variable genes. Kabat, H. A., et al., Sequences of Proteins of Immunological Interest, 4th Ed. (U.S. Dept. Health and Human Services, Bethesda, Md., 1987). Once the animal CDRs and FR are identified, the CDRs are grafted onto human heavy chain variable region framework by the use of synthetic oligonucleotides and polymerase chain reaction (PCR) recombination. Codons for the animal heavy chain CDRs, as well as the available human heavy chain variable region framework, are built in four (each 100 bases long) oligonucleotides. Using PCR, a grated DNA sequence of 400 bases is formed that encodes for the recombinant animal CDR/human heavy chain FR protection.
  • The immunogenic stimulus presented by the monoclonal antibodies so produced may be further decreased by the use of Pharmacia's (Pharmacia LKB Biotechnology, Sweden) “Recombinant Phage Antibody System” (RPAS), which generated a single-chain Fv fragment (ScFv) which incorporates the complete antigen-binding domain of the antibody. In the RPAS, antibody variable heavy and light chain genes are separately amplified from the hybridoma mRNA and cloned into an expression vector. The heavy and light chain domains are co-expressed on the same polypeptide chain after joining with a short linker DNA which codes for a flexible peptide. This assembly generated a single-chain Fv fragment (ScFv) which incorporates the complete antigen-binding domain of the antibody. Compared to the intact monoclonal antibody, the recombinant ScFv includes a considerably lower number of epitopes, and thereby presents a much weaker immunogenic stimulus when injected into humans.
  • The antibodies can be formulated in standard pharmaceutical carriers for administration to patients in need thereof. These include saline, phosphate buffered saline, and other aqueous carriers, and liposomes, polymeric microspheres and other controlled release deliver devices, as are well known in the art. The antibodies can also be administered with adjuvant, such as muramyl dipeptide or other materials approved for use in humans (Freund's adjuvant can be used for administration of antibody to animals). In the preferred embodiment, antibodies are immobilized to a solid support, such as the SEPHAROSE™ column in the examples, using standard techniques such as cyanogen bromide or commercially available kits for coupling of proteins to membranes formed of materials such as nitrocellulose or polycarbonate.
  • Treatment is conducted over a period of time until a positive indication is observed. This is typically based on diagnostic tests which show that there has been some reduction in tumor size or which suggests tumor inflammation. The patient is preferably treated daily for three weeks, diagnostic tests conducted to verity that there has been shrinkage of the tumors and/or inflammation, then the treatment regime is repeated.
  • Surgical (or vacuum) removal of necrotic material may be required prior to or during treatment to avoid toxicity associated with high tumor burden.
  • II. Treatment with Adjuvant Therapies
  • It would clearly be advantageous to cause complete remissions. Based on the presumed mechanism that the process is removing immune inhibitors produced by the tumors, especially inhibitors of cytokines and other immune mediators, it is possible to treat the patients with adjuvant or combination therapies, that enhance the results achieved with the ant6ibodies to TNF receptors. These include anti-angiogenic compounds, such as thalidomide, procoagulant compounds, cytokines and other immunostimulants. Standard chemotherapeutic agents and/or radiation can also be used with the ultrapheresis with the antibody treatment.
  • A. Anti-Angiogenic Compounds
  • Any anti-angiogenic compound can be used. Exemplary anti-angiogenic compounds include O-substituted fumagillol and derivatives thereof, such as TNP-470, described in U.S. Pat. Nos. 5,135,919, 5,698,586, and 5,290,807 to Kishimoto, et al.; angiostatin and endostatin, described in U.S. Pat. No. 5,290,807, 5,639,725 and 5,733,876 to O'Reilly; thalidomide, as described in U.S. Pat. Nos. 5,629,327 and 5,712,291 to D'Amato; and other compounds, such as the anti-invasive factor, retinoic acid, and paclitaxel, described in U.S. Pat. No. 5,716,981 to Hunter, et al., and the metalloproteinase inhibitors described in U.S. Pat. No. 5,713,491 to Murphy, et al. Thalidomide is administered once daily, 200 mg orally.
  • B. Procoagulant Compounds
  • Protein C is a vitamin K-dependent plasma protein zymogen to a serine protease. Upon activation it becomes a potent anticoagulant. Activated protein C acts through the specific proteolysis of the procoagulant cofactors, factor VIIIa and factor Va. This activity requires the presence of another vitamin K-dependent protein, protein S, calcium and a phospholipid (presumably cellular) surface. As described in Hemostasis and Thrombosis: Basic Principles and Clinical Practice 2nd Ed., Colman, R. W., et al., p. 263 (J. B. Lippincott, Philadelphia, Pa. 1987), protein C circulates in a two-chain form, with the larger, heavy chain bound to the smaller light chain through a single disulfide link. Protein C is activated to activated protein C (APC). Thrombin is capable of activating protein C by the specific cleavage of the Arg12-Leu13 bond in the heavy chain. In vivo, in the presence of physiological concentrations of calcium, the rate of this activation is enhanced dramatically when thrombin is bound to the endothelial cell cofactor, thrombomodulin. Matschiner, et al., Current Advances in Vitamin K Research, pp. 135-140, John W. Suttie, ed. (Elsevier Science Publishing Co., Inc. 1988) have further reviewed the role of the Vitamin K dependent proteins in coagulation.
  • Blockage of the natural anticoagulant pathways, in particular the protein C pathway, uses the natural procoagulant properties of the tumor to target the tumor capillaries for microvascular thrombosis, leading to hemorrhagic necrosis of the tumor, as described in U.S. Pat. No. 5,147,638 to Esmon, et al. Examples of such compounds include anti-protein C and anti-protein S.
  • C. Cytokines
  • The biologic activity and clinical effectiveness of pro-inflammatory cytokines is augmented by ultrapheresis in the patient with cancer and other states of acquired immune tolerance Specifically, both TNF alpha and TNF beta, in doses of between approximately 100 to 500 micrograms per meter squared body surface area (M2BSA), can enhance the immune reaction in aggressive tumors. Monocyte and lymphocyte activation is augmented by INF-alpha, INF-beta and gamma. The IL-1 and IL-2 receptor antagonists are removed by ultrapheresis and thereby upregulate the in vivo activity of these cytokines. An 80 kD glycoprotein, which is responsible for inhibiting blastoid transformation in advanced malignancy, chronic infectious disease and pregnancy, has recently been found, and appears to be responsible for the loss of delayed hypersensitivity reactions in these diseases, which is removed by this process. This is significant because in removing this type of suppression, vaccines of all types will work better. Dosage regimes for IFN-alpha and beta are 3 M units subcutaneous three times a week up to 20 M units/M2 BSA daily. Interferon-gamma is administered in a dosage of between 100 to 1000 micgms per day.
  • D. Chemotherapeutic Agents
  • Preferred chemotherapeutic agents are those which are synergistic with TNF, for example, alkylating agents, doxyrubicin, carboplatinum, cisplatinum, and tomoxifen. Tamoxifen plays a role not only in blocking of estrogen receptors but also certain growth factor receptors such as epidermal derived growth factor (“EDGF”), fibroblast derived growth factor (“FDGF”), tumor derived growth factor (“TDGF”), TDGF-β and platelet derived growth factor (“PDGF”) and therefore may be complementary to inflammation against cancers provoked by ultrapheresis.
  • E. Radiation
  • Radiation therapy is destructive of normal tissue, causing tumors to die partially by an inflammatory attack. Ultrapheresis allows the use of lower doses of radiation to kill residual tumor cells and spare normal tissue. In a preferred method, ultrapheresis is used as the initial therapy, followed by radiation at approximately one-half of the normal dosages. It is well established that TNF kills tumor cells by generating free oxygen radicals, hydroxyl radicals and halide ions, and that radiation therapy generates carbonium ions in tissue. Therefore the combination of the two is more effective in killing cancer cells than either alone.
  • III. EXAMPLES Example 1 Treatment of a Patient with Ultrapheresis having Antibodies Immobilized on the Filter
  • Materials and Methods
  • Monoclonal antibody was obtained from R&D Systems, Minneapolis, Minn., and purified for administration to a patient. This antibody is reactive with TNF R1 and R2 inhibitors.
  • A filtration system was assembled using an Eva Flux 4 A filter as the primary filter to remove ultrafiltrate containing these inhibitors from the cancer patient's blood. Monoclonal antibody in a dose of 1 mg per liter of normal ultrafiltrate of the monoclonal antibody and 1 mg of the $2 monoclonal antibody were added to that replacement solution. In this circuit the ultrafiltrate of the initial 4 A filter was delivered by a separate blood pump to a Kuraray 3 A filter. The retentate of the 3A filter was then discarded and the ultrafiltrate of the 3A filter was metered back into the filtered blood from the 4 A filter as replacement solution. To make the discard; i.e., the retentate of the 3 A filter, normal ultrafiltrate with monoclonal antibody added to it was metered into the intra circuit between the 4 A and 3 A filters.
  • Results
  • Addition of the monoclonal antibodies to ultrafiltrated cancer sera that possess elevated levels of the inhibitors decreases the level of detectable inhibitor by Elias Assay to zero.
  • Addition of the monoclonal antibodies to the replacement fluid following ultrapheresis led to an increased reduction of both the soluble receptor to TNF R1 and R2 in the ultrafiltrate of the second filter.
  • The purpose of this was to test whether or not this murine monoclonal antibody could capture the inhibitor and aid in its removal from blood since the complex of antibody and antigen could not pass through the pores of the 3 A filter and thus be discarded in the retentate of the 3A filter. This was considerably more effective than the single separation technique and replacement with normal ultrafiltrate. There was also a heightened tumor specific inflammatory response by doing this and an increased rate of tumor destruction. These experiments strongly indicate that the monoclonal antibody, preferably humanized to 97% to 99% human form by substituting human constant regions for human constant regions on the antibody, preserve its capturing and neutralizing capability with the murine variable regions of the antibody and use the antibody as the therapeutic drug in clinical trials with a very high expectation that it would neutralize soluble receptors to TNF and cause tumor destruction in a human.
  • Example 2 Treatment of a Patient with mAb to TNF Receptors
  • A patient with vaginal metastasis of colon cancer was treated for one week with a three hour infusion of monoclonal antibody to TNF receptor 1 and TNF receptor 2. This led to a 75% reduction in the tumor size within one week.
  • Example 3 Treatment of Melanoma Patient
  • A procedure is described in case report form, that utilizes apheresis and immunological affinity chromatography to treat a melanoma patient with short term need and weakening long term prognosis.
  • Previous studies utilizing ultrafiltration, with selective pore sieving by passing patient's plasma through cartridges, have been shown to reduce sTNF-R1 and R2 levels. The period of this procedure seems to be of sufficient length to allow TNF to rebound and selectively produce apoptosis or membrane disarray of melanoma cells, Gatanaga T., et al., Identification of TNF-LT blocking factor(s) in the serum and ultrafiltrates of human cancer patients, Lymphokine Res 1990; 9:225-9. Instead of using ultrafiltrate cartridges, this apheresis system was coupled to Sepharose® gel columns in parallel, one of which contained monoclonal human anti TNF-R1 and the second anti TNF-R2. The concept of affinity chromatography preparations has been technically available for protein separation and purification, and improved upon over the past 30 years, Ey, P. L., et al., Isolation of pure IgG1, IgG2a, and IgG2b. immunoglobulins from mouse serum using protein A-Sepharose, Immunochemistry 1978; 15:429-436. This type of device represents one of the few examples of linking in vivo production of TNF inhibitors to in vitro removal and return of the purified extracted plasma to the patient to prevent fluid reduction.
  • The patient is a 55 year old Russian gentleman with metastatic melanoma. The patient smoked 2-3 packs of cigarettes a day for some 20 years. He quit this habit several years ago. He was also a heavy alcohol user in years past but had decreased his intake to 1-2 glasses of wine a day. Review of his medications on this date revealed methylprednisolone 4 mg in AM and 4 mg in PM. Apparently this was being taken as replacement therapy for adrenal cortical suppression that was graded iatrogenically at the time of the treatment of his alveolitis (see below). He was additionally taking narcotic analgesics. As a child he suffered the usual childhood diseases, denies rheumatic fever, scarlet fever or diphtheria. As an adult he has had no major medical illnesses save those described above. He has had no other major surgeries in the past and has no known allergies.
  • His history of present illness began in November of 1995 when he noted growth of a right facial naevus which bled and enlarged over the period of one year. This was treated initially by cryotherapy. It regrew within two months and was excised. Histology was that of a malignant melanoma (Clark's level unknown). Staging work up at the time was negative and included CT scans of the head, neck, chest and abdomen. He remained disease free until March of 1996 when he developed right cervical and right submental adenopathy. Preoperative CT scan of the head, neck, chest and abdomen confirmed the right cervical adenopathy but revealed no other sites of metastases. In June of 1996 he underwent re-excision with a right radical neck dissection. In this material, one lymph node was histologically confirmed to involve melanoma. The patient was treated with a course of Vindesine 3 mg/m2 every three weeks, Dacarbazine 100 mg/m2 every three weeks for four cycles. He subsequently developed cutaneous metastases in the skin of his left shoulder, multiple metastases to the scars within the left anterolateral neck and multiple axillary metastases treated with fifteen subsequent excisions of recurrent metastases. In March of 1999 he was offered a trial of Interleukin-2 but on this developed severe pulmonary toxicity that had a protracted course and was diagnosed as idiopathic fibrosing alveolitis. Interleukin-2 was discontinued and he received radiation therapy to his right neck and axilla for six weeks beginning in the month of May 1999. He developed low back pain in August of 1999. Work up in October of 1999 revealed bone metastasis of the vertebral body of T-11 and subsequent MRI revealed a lytic destructive process in the right transverse process and pedicle of the 11th thoracic vertebra, as well as complete replacement of the vertebral body at T-11. Additional metastases were appreciated in the vertebral body of the 9th thoracic vertebral as well as the 10th. Also there was involvement of L-1 and L-2 vertebral bodies. Tumor seen again on the Mar. 16, 2000 MRI revealed growth posteriorly from the mid body of the 11th thoracic vertebral into the spinal canal by 7.4 to 7.8 mm with posterior displacement of the spinal cord. CT scan of the chest, abdomen and pelvis revealed possible multiple liver metastases but no other suggestion of visceral metastases.
  • The patient was then considered for a trial of UltraPheresis™ in an effort to reduce solubilized receptors to tumor necrosis factor, both sTNF-R1 and sTNF-R2. As facilities for the application of this form of semi-selective plasma exchange did not exist in Moscow at this time, affinity column separation of inhibitors was explored. Monoclonal antibodies against sTNF-R1 and R2 delivered to the Cardiology Research Center in Moscow for Dr. Sergei N. Petrovsky, PhD, head of the group for Affinity Sorbents for Medicine, Pocard, Ltd,. 3-rd Cherepkovskaya str., 15a, Moscow, 121552, Russia. Ninety milligrams of anti sTNF-R1 monoclonal antibody and 180 mg of anti sTNF-R2 monoclonal antibody were then bound with sterile Sepharose® using cyanogen bromide in a glass column previously described for use in the lipopack cholesterol absorbent column technology. The particular methodology used is well described and is commercially available in Russia for the development of these LDL absorbent columns. The columns were prepared under sterile conditions in a GSIO 9,001 facility. They were subjected to endotoxin testing, viral, fungal and bacterial cultures, and prepared for human use under written Informed Consent and under approval of the Kremlin President's Hospital Medical Center.
  • On May 2, 2000 the patient's physical examination was that of a well-developed, well-nourished male who appeared his stated years. Examination of his head revealed a normal hair distribution and texture. His tympanic membranes and external auditory canals were clear. The sclerae and conjunctivae were clear. The pupils were round, reactive to light and accommodation. EOM intact. Funduscopic examination was normal. He had a healed graft over his right inferior cheek and extensive scarring over the right anterolateral neck consistent with his history of prior right radical neck dissection. There were no demonstrable pathologic masses within the skin, the scar, or pathologic nodes appreciated either in the cervical nodes or the supraclavicular fossae bilaterally. His lungs were clear to ausculation and percussion. His precordium demonstrated a non-displaced PMI, a normal S1 and S2 without gallop, murmur or rub. With the right arm exhibited there was 3+lymphedema. The right axilla was poorly examined due to extensive scarring in that area but no palpable nodes were appreciated. His abdomen was mildly obese. His liver and spleen were normal to physical examination. His axillary lymphatics were unremarkable. The genitalia was that of a normal mature male without pathologic mass. The lower extremities revealed no edema, cyanosis or clubbing and exhibited full ROM. His neurologic examination included a normal mental status. Cranial nerves 2-12 were intact. His DTR's were 2+ and symmetric. Motor and sensory testing was normal. His cerebellar examination revealed no dysmetria, dysarthria or dysdiadochokinesia. He was essentially confined to bed due to back pain only, but was able to roll from left to right without assistance. He had been confined to a wheelchair for the antecedent two months due to back pain and was wearing a back brace which was removed for physical exam.
  • His laboratory parameters included a hemoglobin of 8.8 gms, WBC 2,800 with normal differential. His platelet count was 121,000. The comprehensive metabolic panel was unremarkable and alkaline phosphatase was normal.
  • An MRI scan of the patient's 11th thoracic vertebral body revealed a mass placing pressure on the spinal cord. This was taken during the week prior to intensive therapy started in April of 2000 and continuing through May.
  • On the first day an 18 gauge plastic cannula was inserted in the left antecubital vein. A second was established in the right greater saphenous vein of the leg. The patient was connected to a standard Cobe Spectra centrifically based plasma separator. Six hundred cc's of plasma was then harvested and replaced with 5% albumin in saline. The patient's plasma was then pumped over column one which contained 45 mg of anti sTNF-R1 monoclonal antibody and then passed to column two which contained 90 mg of anti sTNF-R2 monoclonal antibody. The material eluted from the column was then analyzed for the level of each inhibitor still in the plasma and 50 cc's of that plasma was then injected into the patient at the end of pheresis to look for any febrile reactions or allergic reactions. He tolerated this with no apparent clinical adverse effect.
  • Subsequent analyses of the patient's plasma and the eluate of the column revealed that the column was able to capture essentially all of the inhibitor presented to it in this 600 ml plasma volume. The patient was maintained in the hospital over night and on the morning of the 4th of May, he was brought from hospital room back to the apheresis suite. He had a comfortable evening and ate a normal dinner and breakfast. The IV's were re-established in the same sites. The patient was re-attached to the Cobe Spectra machine and on this date, 3 liters of plasma was harvested and delivered to the columns as described above in a continuous fashion until 3 liters of plasma was treated.
  • His R1 level before treatment was 1500 and after treatment was 1450. His R2 level before treatment was 5000 and after treatment was 3800 on this date. Again he tolerated the procedure well with no clinical adverse effect and no increase in pain in his back.
  • On the third day the 6th of May, the treatment was repeated. Three liters of plasma were again pheresed over the columns in an identical fashion as described above. His pretreatment R1 was 2300, post treatment R1 was 1600. Pretreatment R2 was 5200, post treatment R2 was 3200. At the end of each treatment the columns were washed with glycine buffer at a pH of 2.5 to elute the bound inhibitor from them and measure them quantitatively. It was determined that at these amounts of treated plasma the columns were not saturated and significant quantities of inhibitor removed.
  • His fourth treatment was on the 7th of May. He was increased to 4 liters of treated plasma. The procedures were repeated each day with gradual escalations in amount of plasma treated to a maximum treated plasma of 8 liters on the May 10th, 11th, 12th, 13th, and 14th. On May 16th, two columns were used in parallel, thus increasing the amount of plasma delivered to each column remained at 30 mls per minute, for a total of 60 mls of plasma per minute. This resulted in a pretreatment R1 of 2600 and a post treatment of 1700. R2 pretreatment was 4250 and went to post treatment of 2700.
  • He was subsequently treated with 8 liters of plasma a day using the double column method. On the 21st of May he had a repeat CAT scan of his spine which revealed complete resolution of tumor. Three days after that, May 24th, he had a repeat MRI which was compared to the pretreatment MRI and confirmed a complete response. The patient was followed carefully in the hospital by his attending physicians as well as attending neurosurgeons, who followed him on a daily basis concerned about tumor bleeding or tumor swelling in his tight and anatomically dangerous places but fortunately the patient enjoyed a complete response with no apparent adverse effect.
  • For the details of daily treatment in terms of volumes, columns, blood flow rates and plasma flow rates see Table 1.
  • The patient has enjoyed an apparent complete response without any significant adverse effect. He was able to get up and walk after the fourth procedure. Two additional courses were planned in an endeavor to consolidate this response. This case is consistent with the observations that a salutatory tumor response can be achieved in melanoma by removing solubilized receptors to TNF. This column is so specific that it removes only sTNF-R1 and R2 and that is the only explanation for the response that this man has had from an oncologic point of view. A profound column yield was observed on the third treatment day for sTNF-R2 with modulation for the remaining treatment days throughout this fifteen day course. R1 peaked on treatment day 7 with the total amount removed of 6 million pg. This also modulated throughout the course of treatments but never approached the 16 million mark set by sTNF-R2.
  • Radiographic examination on the day following his first fifteen day course of apheresis with anti R1 and anti R2 affinity column extraction revealed no melanoma and considerable reduction of the lesion at the 4th lumbar vertebral body. Currently the patient remains active, with good appetite, is walking normally and his back pain is much improved. He has positive anticipation for his second course of apheretic treatments.
  • Example 4 Production of Polyclonal Antibodies to STNF R1 and R2 Preparation of Column for Treatment of Patients
  • Polyclonal antibodies were produced in New Zealand white rabbits injected with recombinant antigen, soluble tumor necrosis factor receptor (“STNF”) R1 and R, injected into the rabbit on a standard immunization protocol, then boosted. 200 mg of polyclonal antibody may be produced against STNF R1 and R2, per liter. The animals will be bled monthly. 200 mg of antibody can be bound safely to 200 mg of AH SEPHAROSE™ beads. The binding is done with ethanolamine and periodate. Binding is therefore excellent. This matrix is then placed in a 200 mg polycarbonate column. Each step is done in an aseptic fashion and the final product is then terminally sterilized with standard radiation protocols and subjected to USDA standard testing for pyrogen and infectious agents.
  • This amount of antibody is enough to remove STNF R1 and STNF R2 in human extracellular water sufficient to reduce the level of 10,000 pg per ml to under 1,000 pg per ml in two to three hours of plasma exchange.
  • The use of the columns to reduce inhibitor levels to less than 1000 pg/ml over a period of at least three weeks has resulted in remissions of between 40 and 90% in non-small cell lung cancer, breast cancer and melanoma patients. It is therefore predictable that the treatment results in a rather consistent tumor specific inflammatory response and the majority of patients having the most common tumor types, including breast, small cell lung, colon, ovarian, hepatic, melanoma, and renal cell carcinoma as well as ovarian and endometrial cancers should respond to the treatment. In combination with antibodies against vascular endothelial growth factor receptor and/or epidermal growth factor receptor and/or antibodies against fibroblast derived growth factor and transforming growth factor receptor, either singularly or in combination, the treatment is expected to produce excellent responses in these tumor types and may play a role in the clinical management of hematopoietic disorders as well.
  • The methods and systems disclosed herein are useful for treatment of patients with cancer, immune-mediated disorders, chronic parasitism, some viral diseases especially viral diseases such as HIV which cause immunosuppresion, and other disorders characterized by elevated levels of TNF receptors or inhibitors to IL-2, IL-6, gamma interferon, or other pro-inflammatory signals as well as white cell activation. An example demonstrates efficacy in treating a cancer patient.
  • Modifications and variations of the method and compositions described herein will be obvious to those skilled in the art. Such modifications and variations are intended to come within the scope of the appended claims.

Claims (12)

1. A method for inducing an immune response against transformed, infected or diseased tissue in a patient comprising
contacting the blood, plasma or one or more components of the blood of a patient in need thereof with a column or filter having immobilized therein molecules binding to soluble cytokine receptor molecules, wherein the cytokine is selected from the group consisting of GM-CSF, erythropoietin, thrombopoetin, G-CSF, M-CSF and SCF, wherein the binding molecules are selected from the group consisting of antibodies or antibody fragments and soluble cytokine molecules, wherein binding of the soluble cytokine receptors prevents the soluble cytokine receptors from binding to cytokines in the tissue to be treated, until an immune response is induced in the transformed, infected, or diseased tissue.
2. The method of claim 1 wherein the tissue is a solid tumor.
3. The method of claim 1 wherein the disease is a viral or parasitic disease causing immunosuppression.
4. The method of claim 1 wherein the molecule is an antibody to the soluble cytokine receptor.
5. The method of claim 1 further comprising treating the tissue with an agent selected from the group consisting of anti-angiogenic compounds, procoagulant compounds, cytokines, chemotherapeutic agents, and radiation.
6. (canceled)
7. The method of claim 1 wherein the soluble cytokine receptor molecules are selected from the group consisting of soluble tissue factor receptor 1 (“sTNFR-1”) and soluble tissue necrosis factor receptor-2 (“sTNFR-2”).
8. The method of claim 1 wherein the cytokine receptor molecules are removed by binding to antibodies or antibody fragments immunoreactive with the cytokine receptor molecules.
9. The method of claim 8 wherein the soluble cytokine receptor molecules or antibodies or antibody fragments are immobilized in a filter or column through which the patient's blood or plasma or one or more components thereof is circulated prior to being returned to the patient.
10. The method of claim 4 wherein the antibodies are humanized.
11. The method of claim 1 comprising
contacting the blood, plasma or components thereof with antibodies or antibody fragments immobilized in a sterile endotoxin free extracorporeal device.
12-16. (canceled)
US11/153,524 1998-05-22 2005-06-14 Method and system to remove cytokine inhibitor in patients Abandoned US20050244371A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/153,524 US20050244371A1 (en) 1998-05-22 2005-06-14 Method and system to remove cytokine inhibitor in patients

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US09/083,307 US6620382B1 (en) 1998-05-22 1998-05-22 Method and compositions for treatment of cancers
US09/316,226 US6231536B1 (en) 1998-05-22 1999-05-21 Method and compositions for treatments of cancers
US16469599P 1999-11-10 1999-11-10
US09/699,003 US7854717B1 (en) 1998-05-22 2000-10-26 Method and compositions for treatment of cancers
US09/709,045 US8197430B1 (en) 1998-05-22 2000-11-10 Method and system to remove cytokine inhibitor in patients
US11/153,524 US20050244371A1 (en) 1998-05-22 2005-06-14 Method and system to remove cytokine inhibitor in patients

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
US09/699,003 Continuation-In-Part US7854717B1 (en) 1998-05-22 2000-10-26 Method and compositions for treatment of cancers
US09/709,045 Continuation US8197430B1 (en) 1998-05-22 2000-11-10 Method and system to remove cytokine inhibitor in patients

Publications (1)

Publication Number Publication Date
US20050244371A1 true US20050244371A1 (en) 2005-11-03

Family

ID=46177762

Family Applications (3)

Application Number Title Priority Date Filing Date
US09/709,045 Expired - Fee Related US8197430B1 (en) 1998-05-22 2000-11-10 Method and system to remove cytokine inhibitor in patients
US11/153,524 Abandoned US20050244371A1 (en) 1998-05-22 2005-06-14 Method and system to remove cytokine inhibitor in patients
US11/929,340 Expired - Fee Related US8133490B2 (en) 1998-05-22 2007-10-30 Method and system to remove cytokine inhibitors in patients

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US09/709,045 Expired - Fee Related US8197430B1 (en) 1998-05-22 2000-11-10 Method and system to remove cytokine inhibitor in patients

Family Applications After (1)

Application Number Title Priority Date Filing Date
US11/929,340 Expired - Fee Related US8133490B2 (en) 1998-05-22 2007-10-30 Method and system to remove cytokine inhibitors in patients

Country Status (1)

Country Link
US (3) US8197430B1 (en)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7854717B1 (en) * 1998-05-22 2010-12-21 Biopheresis Technologies, Inc. Method and compositions for treatment of cancers
US8133490B2 (en) 1998-05-22 2012-03-13 Biopheresis Technologies, Inc. Method and system to remove cytokine inhibitors in patients
US10086126B2 (en) * 2009-12-01 2018-10-02 Exthera Medical Corporation Methods for removing cytokines from blood with surface immobilized polysaccharides
US10188783B2 (en) 2005-12-13 2019-01-29 Exthera Medical Corporation Method for extracorporeal removal of pathogenic microbe, an inflammatory cell or an inflammatory protein from blood
US10457974B2 (en) 2013-11-08 2019-10-29 Exthera Medical Corporation Methods for diagnosing infectious diseases using adsorption media
US10537280B2 (en) 2011-02-15 2020-01-21 Exthera Medical Corporation Device and method for removal of blood-borne pathogens, toxins and inflammatory cytokines
US10639413B2 (en) 2013-06-24 2020-05-05 Exthera Medical Corporation Blood filtration system containing mannose coated substrate
US10786615B2 (en) 2016-03-02 2020-09-29 Exthera Medical Corporation Method for treating drug intoxication
US10857283B2 (en) 2014-09-22 2020-12-08 Exthera Medical Corporation Wearable hemoperfusion device
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
US20220054726A1 (en) * 2019-11-19 2022-02-24 Immunicom, Inc. System and method for removal of immune inhibitors from biological fluids
US11266772B2 (en) 2012-06-13 2022-03-08 Exthera Medical Corporation Use of heparin and carbohydrates to treat cancer
CN114650852A (en) * 2019-11-19 2022-06-21 英谬免疫股份有限公司 System and method for removing immunosuppressive agents from biological fluids
US11844895B2 (en) 2014-04-24 2023-12-19 Exthera Medical Corporation Method for removing bacteria from blood using high flow rate
US11911551B2 (en) 2016-03-02 2024-02-27 Exthera Medical Corporation Method for treating drug intoxication

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102004014983A1 (en) * 2004-03-26 2005-10-20 Univ Stuttgart Recombinant polypeptides of the members of the TNF ligand family and their use
WO2005107802A2 (en) * 2004-04-30 2005-11-17 Biopheresis Technologies, Llc Method and system to remove soluble tnfr1, tnfr2, and il2 in patients
US8764695B2 (en) * 2012-09-28 2014-07-01 Isaac Eliaz Reduction of galectin-3 levels by plasmapheresis
WO2015130737A2 (en) 2014-02-28 2015-09-03 Parker-Hannifin Corporation Apheresis system
CA2962251A1 (en) 2014-10-03 2016-04-07 Ntercept, Llc Compositions and methods for inhibiting the biological activity of soluble biomolecules
CN108135850A (en) 2015-07-29 2018-06-08 纳米提克斯有限责任公司 For removing the modular combination object of soluble biomolecule and its correlation technique
EP3565604A4 (en) 2017-01-04 2020-09-09 Nanotics, LLC Methods for assembling scavenging particles

Citations (83)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4116589A (en) * 1977-04-15 1978-09-26 Avco Corporation Extracorporeal pulsatile blood pump comprised of side by side bladders
US4189470A (en) * 1973-01-30 1980-02-19 Bio-Response, Inc. Method for the continuous removal of a specific antibody from the lymph fluid in animals and humans
US4191182A (en) * 1977-09-23 1980-03-04 Hemotherapy Inc. Method and apparatus for continuous plasmaphersis
US4350156A (en) * 1980-05-29 1982-09-21 Japan Foundation For Artificial Organs Method and apparatus for on-line filtration removal of macromolecules from a physiological fluid
US4375414A (en) * 1971-05-20 1983-03-01 Meir Strahilevitz Immunological methods for removing species from the blood circulatory system and devices therefor
US4439332A (en) * 1978-08-14 1984-03-27 American Cyanamid Company Stable emulsion copolymers of acrylamide and ammonium acrylate for use in enhanced oil recovery
USRE31688E (en) * 1977-09-23 1984-09-25 Hemotherapy, Inc. Method and apparatus for continuous plasmapheresis
US4512763A (en) * 1981-05-04 1985-04-23 Gamma Medical Products, Inc. Method and apparatus for selective removal of constituents of blood
US4581010A (en) * 1981-03-24 1986-04-08 Skurkovich Simon V Method of immonosuppression after transplantation of cells, tissues and organs
US4605394A (en) * 1982-12-03 1986-08-12 Simon V. Skurkovich Methods for the treatment of pathological conditions by removing interferon from the organism
US4614513A (en) * 1984-08-13 1986-09-30 Fred Hutchinson Cancer Research Center Method and apparatus for treatment to remove immunoreactive substances from blood
US4634417A (en) * 1982-12-06 1987-01-06 Georgetown University Process for treatment of tumors and apparatus therefor
US4664913A (en) * 1982-05-24 1987-05-12 Xoma Corporation Method for treating plasma for transfusion
US4801449A (en) * 1985-01-11 1989-01-31 Imre Corporation Method for treatment of Kaposi's sarcoma
US4824432A (en) * 1981-03-24 1989-04-25 S.V.S. Laboratories, Inc. Method for treating AIDS and other immune deficiencies and immune disorders
US4863611A (en) * 1987-04-30 1989-09-05 Massachusetts Institute Of Technology Extracorporeal reactors containing immobilized species
US4865841A (en) * 1987-10-23 1989-09-12 Imre Corporation Methods and compositions for transient elimination of humoral immune antibodies
US5037649A (en) * 1985-01-11 1991-08-06 Imre Corporation Method for treatment of HIV-infected patients
US5078673A (en) * 1988-11-14 1992-01-07 Neorx Corporation Selective removal of radiolabeled antibodies
US5135919A (en) * 1988-01-19 1992-08-04 Children's Medical Center Corporation Method and a pharmaceutical composition for the inhibition of angiogenesis
US5147638A (en) * 1988-12-30 1992-09-15 Oklahoma Medical Research Foundation Inhibition of tumor growth by blockade of the protein C system
US5290807A (en) * 1989-08-10 1994-03-01 Children's Medical Center Corporation Method for regressing angiogenesis using o-substituted fumagillol derivatives
US5403917A (en) * 1992-10-12 1995-04-04 B. Braun Melsungen, Ag Process for the quantitative selective removal or preparative isolation of tumour necrosis factor (TNF) or/and lipopolysaccharides (LPS) from aqueous liquids
US5523096A (en) * 1993-03-16 1996-06-04 Applied Immune Sciences, Inc. Removal of selected factors from whole blood or its components
US5597899A (en) * 1993-03-29 1997-01-28 Hoffmann-La Roche Inc. Tumor necrosis factor muteins
US5605690A (en) * 1989-09-05 1997-02-25 Immunex Corporation Methods of lowering active TNF-α levels in mammals using tumor necrosis factor receptor
US5610279A (en) * 1989-09-12 1997-03-11 Hoffman-La Roche Inc. Human TNF receptor
US5621077A (en) * 1989-06-01 1997-04-15 Yeda Research And Development Co. Ltd. Soluble IFN-β2/IL-6 binding protein its preparation, and pharmaceutical compositions containing it
US5626843A (en) * 1993-02-26 1997-05-06 Advanced Biotherapy Concepts, Inc. Treatment of autoimmune diseases, including AIDS, by removel of interferons, TNFs and receptors therefor
US5629327A (en) * 1993-03-01 1997-05-13 Childrens Hospital Medical Center Corp. Methods and compositions for inhibition of angiogenesis
US5639725A (en) * 1994-04-26 1997-06-17 Children's Hospital Medical Center Corp. Angiostatin protein
US5643732A (en) * 1971-05-20 1997-07-01 Strahilevitz; Meir Immunological assay methods
US5705615A (en) * 1994-10-06 1998-01-06 Beth Israel Deaconess Medical Center Antibodies specific for HTm4
US5713491A (en) * 1993-11-12 1998-02-03 Idv Operations Ireland Limited Pourer for pouring liquids from two containers
US5716981A (en) * 1993-07-19 1998-02-10 Angiogenesis Technologies, Inc. Anti-angiogenic compositions and methods of use
US5730713A (en) * 1993-03-16 1998-03-24 Rhone-Poulenc Rorer Pharmaceuticals Inc. Removal of selected factors from whole blood or its components
US5736138A (en) * 1990-02-28 1998-04-07 Klaus Pfizenmaier Monoclonal antibodies with specific binding against membrane proteins on human cells, and pharmaceutical compositions containing them
US5753227A (en) * 1993-07-23 1998-05-19 Strahilevitz; Meir Extracorporeal affinity adsorption methods for the treatment of atherosclerosis, cancer, degenerative and autoimmune diseases
US5861483A (en) * 1996-04-03 1999-01-19 Pro-Neuron, Inc. Inhibitor of stem cell proliferation and uses thereof
US5869047A (en) * 1996-10-22 1999-02-09 Blake Laboratories, Inc. Methods for therapeutically treating immunocomprised persons
US5888511A (en) * 1993-02-26 1999-03-30 Advanced Biotherapy Concepts, Inc. Treatment of autoimmune diseases, including AIDS
US5910252A (en) * 1993-02-12 1999-06-08 Cobe Laboratories, Inc. Technique for extracorporeal treatment of blood
US5919898A (en) * 1995-01-27 1999-07-06 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Absorbent for removing interleukins and tumor necrosis factor, and process for removing the same
US5932704A (en) * 1992-11-19 1999-08-03 Dana-Farber Cancer Institute Antibodies for GM-CSF receptor and uses thereof
US6017527A (en) * 1996-07-10 2000-01-25 Immunex Corporation Activated dendritic cells and methods for their activation
USRE36755E (en) * 1989-09-05 2000-06-27 Immunex Corporation DNA encoding tumor necrosis factor-α and -β receptors
US6197289B1 (en) * 1997-07-01 2001-03-06 Terumo Cardiovascular Systems Corporation Removal of biologically active agents
US6221614B1 (en) * 1997-02-21 2001-04-24 The Regents Of The University Of California Removal of prions from blood, plasma and other liquids
US6231536B1 (en) * 1998-05-22 2001-05-15 M. Rigdon Lentz Method and compositions for treatments of cancers
US6245038B1 (en) * 1997-01-07 2001-06-12 Helmut Borberg Method for treatment of ophthalmological diseases
US6262127B1 (en) * 1993-08-27 2001-07-17 Novartis Ag Polymeric matrices and their uses in pharmaceutical compositions
US20010010818A1 (en) * 1998-12-09 2001-08-02 Engle Steven B. Methods and formulations for reducing circulating antibodies
US6287516B1 (en) * 1998-07-10 2001-09-11 Immunocept, L.L.C. Hemofiltration systems, methods, and devices used to treat inflammatory mediator related disease
US6379708B1 (en) * 1999-11-20 2002-04-30 Cytologic, Llc Method for enhancing immune responses in mammals
US20020058031A1 (en) * 2000-09-19 2002-05-16 Tung Hsiaoho Edward Methods for preparing diagnostic reagents using antibody preparation
US20020086276A1 (en) * 2000-12-28 2002-07-04 Srivastava Pramod K. Immunotherapeutic methods for extracorporeal modulation of CD36 and its ligands
US6428790B1 (en) * 1995-04-27 2002-08-06 The United States Of America As Represented By The Secretary Department Of Health And Human Services Cyanovirin conjugates and matrix-anchored cyanovirin and related compositions and methods of use
US20020107469A1 (en) * 2000-11-03 2002-08-08 Charles Bolan Apheresis methods and devices
US6432405B1 (en) * 1991-03-15 2002-08-13 Duke University Method of inhibiting HIV infection with CD44 and anti-CD44 antibodies
US20020111577A1 (en) * 2001-02-09 2002-08-15 Laksen Sirimanne Extra-corporeal vascular conduit
US6528057B1 (en) * 1998-08-31 2003-03-04 Julian L. Ambrus Method for removal of HIV and other viruses from blood
US20030073822A1 (en) * 2001-07-20 2003-04-17 Jonas Lofling Blood group antigen fusion polypeptides and method of use thereof
US6561997B1 (en) * 1999-04-23 2003-05-13 The Regents Of The University Of Michigan Extracorporeal fluid circuit and related methods
US20030118584A1 (en) * 1998-11-18 2003-06-26 G.D. Searle & Co. Restoration of platelet aggregation by antibody administration after GPIIB/IIIa antagonist treatment
US20030125657A1 (en) * 1995-11-15 2003-07-03 Robert Koll Treatment of cardiomyopathy by removal of autoantibodies
US20030127390A1 (en) * 1998-12-29 2003-07-10 Occulogix Corporation Rheological treatment methods and related apheresis systems
US20030133929A1 (en) * 2000-06-29 2003-07-17 Cham Bill E Method of treating infectious diseases
US20030138349A1 (en) * 1998-10-16 2003-07-24 Mission Medical, Inc. Blood processing system
US6602993B2 (en) * 1989-05-18 2003-08-05 Yeda Research And Development Co. Ltd. DNA molecule encoding TNF binding ligands and vectors and host cells containing the DNA molecule
US20030148404A1 (en) * 2000-07-27 2003-08-07 Ramot University Authority For Applied Research & Industrial Development Ltd. Peptides and substances, methods and devices using same for diagnosing and treating neurodegenerative disorders
US6607723B1 (en) * 1991-08-23 2003-08-19 Alberta Research Council Methods and compositions for attenuating antibody-mediated xenograft rejection in human recipients
US6607501B2 (en) * 2001-05-14 2003-08-19 Reynolds G. Gorsuch Process and apparatus for utilization of in vivo extracted plasma with tissue engineering devices, bioreactors, artificial organs, and cell therapy applications
US20030163077A1 (en) * 2000-06-15 2003-08-28 Sung-Teh Kim Automatic dialyzer and dialyzing method
US6627151B1 (en) * 1997-06-13 2003-09-30 Helmut Borberg Method for treatment diseases associated with a deterioration of the macrocirculation, microcirculation and organ perfusion
US6685664B2 (en) * 2001-06-08 2004-02-03 Chf Solutions, Inc. Method and apparatus for ultrafiltration utilizing a long peripheral access venous cannula for blood withdrawal
US20040054315A1 (en) * 2000-05-23 2004-03-18 Chf Solutions, Inc. Method and apparatus for peripheral vein fluid removal in heart failure
US6774102B1 (en) * 1999-09-29 2004-08-10 Gambro Dialysatoren Gmbh & Co. Kg Extracorporeal endotoxin removal method
US6866846B1 (en) * 1995-10-05 2005-03-15 Privates Institut Bioserv Gmbh Patient-specific immunoadsorbers for the extracorporeal apheresis and methods for their preparation
US6878127B2 (en) * 2001-04-10 2005-04-12 Renaltech International, Llc Devices, systems, and methods for reducing levels of pro-inflammatory or anti-inflammatory stimulators or mediators in the blood
US20070065514A1 (en) * 2005-09-22 2007-03-22 Howell Mark D Method for enhancing immune responses in mammals
US7196070B2 (en) * 1995-08-03 2007-03-27 Johns Hopkins University School Of Medicine Prophylactic and therapeutic treatment of the ductal epithelium of a mammary gland for cancer
US20080075690A1 (en) * 2006-09-22 2008-03-27 Mark Douglas Howell Method for enhancing immune responses in mammals
US7368295B2 (en) * 2001-08-31 2008-05-06 Fraunhofer-Gesellschaft Zur Foderung Der Angewandten Forschung E.V. Nanoparticles comprising biologically active TNF which is immobilized on the same

Family Cites Families (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4787974A (en) 1981-06-29 1988-11-29 Ambrus Clara M Blood purification
BR8205658A (en) 1981-10-02 1983-08-30 Du Pont FILTER PLASMA PHERESIS PROCESS AND APPLIANCE
DE3302384A1 (en) 1983-01-25 1984-07-26 Michael J. Lysaght Plasma filter unit for removing pathological plasma molecules
US4486282A (en) 1983-02-22 1984-12-04 University Patents, Inc. Precipitation of proteins from salt-containing proteinaceous fluids employing a desalting treatment, and use thereof in selective plasmapheresis
JPS59168843A (en) 1983-03-14 1984-09-22 ジエルマン サイエンシスインコ−ポレ−テツド Method and filter for sampling serum specimen
US4633417A (en) 1984-06-20 1986-12-30 Step Engineering Emulator for non-fixed instruction set VLSI devices
US4708713A (en) 1984-11-16 1987-11-24 Anisa Medical, Inc. Method and system for removing immunosuppressive components from the blood of mammals
US4828830A (en) * 1986-01-24 1989-05-09 Genentech, Inc. Method and composition for prophylaxis and treatment of viral infections
US4857314A (en) * 1986-07-18 1989-08-15 Health Research , Inc. C-reactive proteins in treatment of animal and human cancers
US4963265A (en) 1988-05-06 1990-10-16 Applied Immunesciences, Inc. Plasma processing device with anaphylatoxin remover
ES2099064T3 (en) 1988-09-01 1997-05-16 Takeda Chemical Industries Ltd DERIVATIVES OF FUMAGILLOL.
US5359037A (en) 1988-09-12 1994-10-25 Yeda Research And Development Co. Ltd. Antibodies to TNF binding protein I
US7264944B1 (en) 1989-04-21 2007-09-04 Amgen Inc. TNF receptors, TNF binding proteins and DNAs coding for them
ATE138204T1 (en) 1990-03-12 1996-06-15 Du Pont CARRIER FOR BIOCHEMICALLY ACTIVE SUBSTANCES
US5340736A (en) 1991-05-13 1994-08-23 The President & Fellows Of Harvard College ATP-dependent protease and use of inhibitors for same in the treatment of cachexia and muscle wasting
EP0589982B1 (en) 1991-06-19 2001-01-17 Boehringer Ingelheim International GmbH Monoclonal antibodies against human tnf-binding protein i (tnf-bp i)
PT528767E (en) * 1991-08-21 2000-06-30 Novartis Ag ANTIBODY DERIVATIVES
ES2136092T3 (en) * 1991-09-23 1999-11-16 Medical Res Council PROCEDURES FOR THE PRODUCTION OF HUMANIZED ANTIBODIES.
ES2182832T3 (en) 1992-10-15 2003-03-16 Toray Industries PROCEDURE FOR THE PRODUCTION OF A CHMII ANTIGEN RECOMBINANT PROTEIN IN MICROORGANISMS.
DE4345200C2 (en) 1993-04-14 1995-07-13 Fresenius Ag Hybridoma cells that form antibodies that are contained in drugs used to treat immune reactions
DE69534187T2 (en) * 1994-05-13 2005-11-17 Miltenyi Biotec Gmbh STERILE AND PYROGEN-FREE COLUMNS COUPLED WITH A PROTEIN FOR BINDING AND REMOVING SUBSTANCES FROM THE BLOOD
DE4435612A1 (en) 1994-10-05 1996-04-11 Braun Melsungen Ag Process for the simultaneous removal of tumor necrosis factor alpha and bacterial lipopolysaccharides from an aqueous liquid
WO1997026930A1 (en) 1996-01-25 1997-07-31 Kaneka Corporation Adsorbent for immunoglobulins and complexes thereof, adsorption method, and adsorption device
US5925633A (en) 1996-03-06 1999-07-20 Synphar Laboraties, Inc. 3-Substituted-4-oxa-1-azabicyclo 3,2,0!heptan-7-one as cysteine protease inhibitors
DE69724241T2 (en) 1996-03-14 2004-06-09 Genentech, Inc., South San Francisco GDNF RECEPTOR AND THEIR USE
DE19624250A1 (en) 1996-06-18 1998-01-02 Peter Ahrenholz Haemodialysis appts
US5980887A (en) 1996-11-08 1999-11-09 St. Elizabeth's Medical Center Of Boston Methods for enhancing angiogenesis with endothelial progenitor cells
RU2130069C1 (en) 1997-03-14 1999-05-10 Институт элементоорганических соединений им.А.Н.Несмеянова РАН Method of virus concentrating
US20020159995A1 (en) 1997-07-30 2002-10-31 Renal Tech International Devices, systems, and methods for reducing levels of pro-inflammatory or anti-inflammatory stimulators or mediators in the blood, generated as a result of extracorporeal blood processing
US20020197250A1 (en) 2001-04-10 2002-12-26 Renal Tech International Biocompatible devices, systems, and methods for reducing levels of pro-inflammatory or anti-inflammatory stimulators or mediators in the blood
US20020197249A1 (en) 2001-04-10 2002-12-26 Renal Tech International Devices, systems, and methods for reducing levels of pro-inflammatory or anti-inflammatory stimulators or mediators in blood products
US6565831B1 (en) 1999-02-24 2003-05-20 Oncolytics Biotech Inc. Methods for preventing reovirus recognition for the treatment of cellular proliferative disorders
US5965394A (en) 1997-09-18 1999-10-12 Incyte Pharmaceuticals, Inc. Human importin alpha homolog
US6824986B1 (en) 1997-10-06 2004-11-30 University Of Cincinnati Methods for measuring in vivo cytokine production
US5817522A (en) 1997-11-12 1998-10-06 Goodman; David B. P. Self-contained assay device and method
US8197430B1 (en) 1998-05-22 2012-06-12 Biopheresis Technologies, Inc. Method and system to remove cytokine inhibitor in patients
AUPP525198A0 (en) 1998-08-13 1998-09-03 Medvet Science Pty. Ltd. Monoclonal antibody inhibitor of GM-CSF, IL-3 and IL-5 and other cytokines and uses thereof
US6982089B2 (en) 1999-02-24 2006-01-03 Tact Ip, Llc Cytokine antagonists for neurological and neuropsychiatric disorders
US6676662B1 (en) 1999-10-20 2004-01-13 Sulzer Spine-Tech Inc. Bone instruments and methods
US6960178B2 (en) 2000-02-02 2005-11-01 Xepmed, Inc. Apparatus for enhanced plasmapheresis and methods thereof
US6554788B1 (en) 2000-06-02 2003-04-29 Cobe Cardiovascular, Inc. Hematocrit sampling system
US20020114728A1 (en) 2001-02-13 2002-08-22 Kulish Victor V. Electronic Sterilizer
US8158106B2 (en) 2001-10-05 2012-04-17 Surmodics, Inc. Particle immobilized coatings and uses thereof
WO2005107802A2 (en) 2004-04-30 2005-11-17 Biopheresis Technologies, Llc Method and system to remove soluble tnfr1, tnfr2, and il2 in patients

Patent Citations (100)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4813924A (en) * 1971-05-20 1989-03-21 Meir Strahilevitz Immunological methods for removing species from the blood circulatory system
US4375414A (en) * 1971-05-20 1983-03-01 Meir Strahilevitz Immunological methods for removing species from the blood circulatory system and devices therefor
US5643732A (en) * 1971-05-20 1997-07-01 Strahilevitz; Meir Immunological assay methods
US5037645A (en) * 1971-05-20 1991-08-06 Meir Strahilevitz Immunological methods for treating schizophrenia
US4834973A (en) * 1971-05-20 1989-05-30 Meir Strahilevitz Immunological methods for treating mammals
US6602502B1 (en) * 1971-05-20 2003-08-05 Meir Strahilevitz Methods and devices for removing species
US4189470A (en) * 1973-01-30 1980-02-19 Bio-Response, Inc. Method for the continuous removal of a specific antibody from the lymph fluid in animals and humans
US4116589A (en) * 1977-04-15 1978-09-26 Avco Corporation Extracorporeal pulsatile blood pump comprised of side by side bladders
US4191182A (en) * 1977-09-23 1980-03-04 Hemotherapy Inc. Method and apparatus for continuous plasmaphersis
USRE31688E (en) * 1977-09-23 1984-09-25 Hemotherapy, Inc. Method and apparatus for continuous plasmapheresis
US4439332A (en) * 1978-08-14 1984-03-27 American Cyanamid Company Stable emulsion copolymers of acrylamide and ammonium acrylate for use in enhanced oil recovery
US4350156A (en) * 1980-05-29 1982-09-21 Japan Foundation For Artificial Organs Method and apparatus for on-line filtration removal of macromolecules from a physiological fluid
US4824432A (en) * 1981-03-24 1989-04-25 S.V.S. Laboratories, Inc. Method for treating AIDS and other immune deficiencies and immune disorders
US4581010A (en) * 1981-03-24 1986-04-08 Skurkovich Simon V Method of immonosuppression after transplantation of cells, tissues and organs
US4512763A (en) * 1981-05-04 1985-04-23 Gamma Medical Products, Inc. Method and apparatus for selective removal of constituents of blood
US4664913A (en) * 1982-05-24 1987-05-12 Xoma Corporation Method for treating plasma for transfusion
US4664913B1 (en) * 1982-05-24 1990-01-30 Xoma Corp
US4605394A (en) * 1982-12-03 1986-08-12 Simon V. Skurkovich Methods for the treatment of pathological conditions by removing interferon from the organism
US4634417A (en) * 1982-12-06 1987-01-06 Georgetown University Process for treatment of tumors and apparatus therefor
US4614513A (en) * 1984-08-13 1986-09-30 Fred Hutchinson Cancer Research Center Method and apparatus for treatment to remove immunoreactive substances from blood
US4801449A (en) * 1985-01-11 1989-01-31 Imre Corporation Method for treatment of Kaposi's sarcoma
US5037649A (en) * 1985-01-11 1991-08-06 Imre Corporation Method for treatment of HIV-infected patients
US4863611A (en) * 1987-04-30 1989-09-05 Massachusetts Institute Of Technology Extracorporeal reactors containing immobilized species
US4865841A (en) * 1987-10-23 1989-09-12 Imre Corporation Methods and compositions for transient elimination of humoral immune antibodies
US5135919A (en) * 1988-01-19 1992-08-04 Children's Medical Center Corporation Method and a pharmaceutical composition for the inhibition of angiogenesis
US5078673A (en) * 1988-11-14 1992-01-07 Neorx Corporation Selective removal of radiolabeled antibodies
US5147638A (en) * 1988-12-30 1992-09-15 Oklahoma Medical Research Foundation Inhibition of tumor growth by blockade of the protein C system
US6602993B2 (en) * 1989-05-18 2003-08-05 Yeda Research And Development Co. Ltd. DNA molecule encoding TNF binding ligands and vectors and host cells containing the DNA molecule
US5621077A (en) * 1989-06-01 1997-04-15 Yeda Research And Development Co. Ltd. Soluble IFN-β2/IL-6 binding protein its preparation, and pharmaceutical compositions containing it
US5290807A (en) * 1989-08-10 1994-03-01 Children's Medical Center Corporation Method for regressing angiogenesis using o-substituted fumagillol derivatives
US5605690A (en) * 1989-09-05 1997-02-25 Immunex Corporation Methods of lowering active TNF-α levels in mammals using tumor necrosis factor receptor
USRE36755E (en) * 1989-09-05 2000-06-27 Immunex Corporation DNA encoding tumor necrosis factor-α and -β receptors
US5808029A (en) * 1989-09-12 1998-09-15 Hoffmann-La Roche Inc. DNA encoding a human TNF binding protein
US5610279A (en) * 1989-09-12 1997-03-11 Hoffman-La Roche Inc. Human TNF receptor
US5736138A (en) * 1990-02-28 1998-04-07 Klaus Pfizenmaier Monoclonal antibodies with specific binding against membrane proteins on human cells, and pharmaceutical compositions containing them
US6432405B1 (en) * 1991-03-15 2002-08-13 Duke University Method of inhibiting HIV infection with CD44 and anti-CD44 antibodies
US6607723B1 (en) * 1991-08-23 2003-08-19 Alberta Research Council Methods and compositions for attenuating antibody-mediated xenograft rejection in human recipients
US5403917A (en) * 1992-10-12 1995-04-04 B. Braun Melsungen, Ag Process for the quantitative selective removal or preparative isolation of tumour necrosis factor (TNF) or/and lipopolysaccharides (LPS) from aqueous liquids
US5932704A (en) * 1992-11-19 1999-08-03 Dana-Farber Cancer Institute Antibodies for GM-CSF receptor and uses thereof
US5910252A (en) * 1993-02-12 1999-06-08 Cobe Laboratories, Inc. Technique for extracorporeal treatment of blood
US5626843A (en) * 1993-02-26 1997-05-06 Advanced Biotherapy Concepts, Inc. Treatment of autoimmune diseases, including AIDS, by removel of interferons, TNFs and receptors therefor
US5888511A (en) * 1993-02-26 1999-03-30 Advanced Biotherapy Concepts, Inc. Treatment of autoimmune diseases, including AIDS
US5629327A (en) * 1993-03-01 1997-05-13 Childrens Hospital Medical Center Corp. Methods and compositions for inhibition of angiogenesis
US5712291A (en) * 1993-03-01 1998-01-27 The Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis
US5730713A (en) * 1993-03-16 1998-03-24 Rhone-Poulenc Rorer Pharmaceuticals Inc. Removal of selected factors from whole blood or its components
US5523096A (en) * 1993-03-16 1996-06-04 Applied Immune Sciences, Inc. Removal of selected factors from whole blood or its components
US5597899A (en) * 1993-03-29 1997-01-28 Hoffmann-La Roche Inc. Tumor necrosis factor muteins
US5716981A (en) * 1993-07-19 1998-02-10 Angiogenesis Technologies, Inc. Anti-angiogenic compositions and methods of use
US6039946A (en) * 1993-07-23 2000-03-21 Strahilevitz; Meir Extracorporeal affinity adsorption devices
US5753227A (en) * 1993-07-23 1998-05-19 Strahilevitz; Meir Extracorporeal affinity adsorption methods for the treatment of atherosclerosis, cancer, degenerative and autoimmune diseases
US6264623B1 (en) * 1993-07-23 2001-07-24 Meir Strahilevitz Extracorporeal affinity adsorption methods for the treatment of atherosclerosis, cancer, degenerative and autoimmune disease
US6569112B2 (en) * 1993-07-23 2003-05-27 Meir Strahilevitz Extracorporeal affinity adsorption device
US6676622B2 (en) * 1993-07-23 2004-01-13 Meir Strahilevitz Extracorporeal affinity adsorption methods for the treatment of atherosclerosis, cancer, degenerative and autoimmune diseases
US20020019603A1 (en) * 1993-07-23 2002-02-14 Meir Strahilevitz Extracorporeal affinity adsorption device
US6262127B1 (en) * 1993-08-27 2001-07-17 Novartis Ag Polymeric matrices and their uses in pharmaceutical compositions
US5713491A (en) * 1993-11-12 1998-02-03 Idv Operations Ireland Limited Pourer for pouring liquids from two containers
US5639725A (en) * 1994-04-26 1997-06-17 Children's Hospital Medical Center Corp. Angiostatin protein
US5792845A (en) * 1994-04-26 1998-08-11 The Children's Medical Center Corporation Nucleotides encoding angiostatin protein and method of use
US5733876A (en) * 1994-04-26 1998-03-31 The Children's Medical Center Corporation Method of inhibiting angiogenesis
US5705615A (en) * 1994-10-06 1998-01-06 Beth Israel Deaconess Medical Center Antibodies specific for HTm4
US5919898A (en) * 1995-01-27 1999-07-06 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Absorbent for removing interleukins and tumor necrosis factor, and process for removing the same
US6428790B1 (en) * 1995-04-27 2002-08-06 The United States Of America As Represented By The Secretary Department Of Health And Human Services Cyanovirin conjugates and matrix-anchored cyanovirin and related compositions and methods of use
US7196070B2 (en) * 1995-08-03 2007-03-27 Johns Hopkins University School Of Medicine Prophylactic and therapeutic treatment of the ductal epithelium of a mammary gland for cancer
US6866846B1 (en) * 1995-10-05 2005-03-15 Privates Institut Bioserv Gmbh Patient-specific immunoadsorbers for the extracorporeal apheresis and methods for their preparation
US20030125657A1 (en) * 1995-11-15 2003-07-03 Robert Koll Treatment of cardiomyopathy by removal of autoantibodies
US5861483A (en) * 1996-04-03 1999-01-19 Pro-Neuron, Inc. Inhibitor of stem cell proliferation and uses thereof
US6017527A (en) * 1996-07-10 2000-01-25 Immunex Corporation Activated dendritic cells and methods for their activation
US5869047A (en) * 1996-10-22 1999-02-09 Blake Laboratories, Inc. Methods for therapeutically treating immunocomprised persons
US6245038B1 (en) * 1997-01-07 2001-06-12 Helmut Borberg Method for treatment of ophthalmological diseases
US6221614B1 (en) * 1997-02-21 2001-04-24 The Regents Of The University Of California Removal of prions from blood, plasma and other liquids
US6627151B1 (en) * 1997-06-13 2003-09-30 Helmut Borberg Method for treatment diseases associated with a deterioration of the macrocirculation, microcirculation and organ perfusion
US6197289B1 (en) * 1997-07-01 2001-03-06 Terumo Cardiovascular Systems Corporation Removal of biologically active agents
US6620382B1 (en) * 1998-05-22 2003-09-16 Biopheresis Technologies, Llc. Method and compositions for treatment of cancers
US6231536B1 (en) * 1998-05-22 2001-05-15 M. Rigdon Lentz Method and compositions for treatments of cancers
US6287516B1 (en) * 1998-07-10 2001-09-11 Immunocept, L.L.C. Hemofiltration systems, methods, and devices used to treat inflammatory mediator related disease
US6528057B1 (en) * 1998-08-31 2003-03-04 Julian L. Ambrus Method for removal of HIV and other viruses from blood
US20030138349A1 (en) * 1998-10-16 2003-07-24 Mission Medical, Inc. Blood processing system
US20030118584A1 (en) * 1998-11-18 2003-06-26 G.D. Searle & Co. Restoration of platelet aggregation by antibody administration after GPIIB/IIIa antagonist treatment
US20010010818A1 (en) * 1998-12-09 2001-08-02 Engle Steven B. Methods and formulations for reducing circulating antibodies
US20030127390A1 (en) * 1998-12-29 2003-07-10 Occulogix Corporation Rheological treatment methods and related apheresis systems
US6561997B1 (en) * 1999-04-23 2003-05-13 The Regents Of The University Of Michigan Extracorporeal fluid circuit and related methods
US6774102B1 (en) * 1999-09-29 2004-08-10 Gambro Dialysatoren Gmbh & Co. Kg Extracorporeal endotoxin removal method
US20020119147A1 (en) * 1999-11-20 2002-08-29 Cytologic, Llc Apparatus for enhancing immune responses in mammals
US6379708B1 (en) * 1999-11-20 2002-04-30 Cytologic, Llc Method for enhancing immune responses in mammals
US20040054315A1 (en) * 2000-05-23 2004-03-18 Chf Solutions, Inc. Method and apparatus for peripheral vein fluid removal in heart failure
US20030163077A1 (en) * 2000-06-15 2003-08-28 Sung-Teh Kim Automatic dialyzer and dialyzing method
US20030133929A1 (en) * 2000-06-29 2003-07-17 Cham Bill E Method of treating infectious diseases
US20030148404A1 (en) * 2000-07-27 2003-08-07 Ramot University Authority For Applied Research & Industrial Development Ltd. Peptides and substances, methods and devices using same for diagnosing and treating neurodegenerative disorders
US20020058031A1 (en) * 2000-09-19 2002-05-16 Tung Hsiaoho Edward Methods for preparing diagnostic reagents using antibody preparation
US20020107469A1 (en) * 2000-11-03 2002-08-08 Charles Bolan Apheresis methods and devices
US20020086276A1 (en) * 2000-12-28 2002-07-04 Srivastava Pramod K. Immunotherapeutic methods for extracorporeal modulation of CD36 and its ligands
US20020111577A1 (en) * 2001-02-09 2002-08-15 Laksen Sirimanne Extra-corporeal vascular conduit
US6878127B2 (en) * 2001-04-10 2005-04-12 Renaltech International, Llc Devices, systems, and methods for reducing levels of pro-inflammatory or anti-inflammatory stimulators or mediators in the blood
US6607501B2 (en) * 2001-05-14 2003-08-19 Reynolds G. Gorsuch Process and apparatus for utilization of in vivo extracted plasma with tissue engineering devices, bioreactors, artificial organs, and cell therapy applications
US20040044301A1 (en) * 2001-06-08 2004-03-04 Chf Solutions, Inc. Method and apparatus for ultrafiltration utilizing a long peripheral access venous cannula for blood withdrawal
US6685664B2 (en) * 2001-06-08 2004-02-03 Chf Solutions, Inc. Method and apparatus for ultrafiltration utilizing a long peripheral access venous cannula for blood withdrawal
US20030073822A1 (en) * 2001-07-20 2003-04-17 Jonas Lofling Blood group antigen fusion polypeptides and method of use thereof
US7368295B2 (en) * 2001-08-31 2008-05-06 Fraunhofer-Gesellschaft Zur Foderung Der Angewandten Forschung E.V. Nanoparticles comprising biologically active TNF which is immobilized on the same
US20070065514A1 (en) * 2005-09-22 2007-03-22 Howell Mark D Method for enhancing immune responses in mammals
US20080075690A1 (en) * 2006-09-22 2008-03-27 Mark Douglas Howell Method for enhancing immune responses in mammals

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7854717B1 (en) * 1998-05-22 2010-12-21 Biopheresis Technologies, Inc. Method and compositions for treatment of cancers
US8133490B2 (en) 1998-05-22 2012-03-13 Biopheresis Technologies, Inc. Method and system to remove cytokine inhibitors in patients
US8197430B1 (en) 1998-05-22 2012-06-12 Biopheresis Technologies, Inc. Method and system to remove cytokine inhibitor in patients
US10188783B2 (en) 2005-12-13 2019-01-29 Exthera Medical Corporation Method for extracorporeal removal of pathogenic microbe, an inflammatory cell or an inflammatory protein from blood
US11065378B2 (en) 2005-12-13 2021-07-20 Exthera Medical Corporation Method for extracorporeal removal of a pathogenic microbe, an inflammatory cell or an inflammatory protein from blood
US10688239B2 (en) 2005-12-13 2020-06-23 Exthera Medical Corporation Method for extracorporeal removal of a pathogenic microbe, an inflammatory cell or an inflammatory protein from blood
US10086126B2 (en) * 2009-12-01 2018-10-02 Exthera Medical Corporation Methods for removing cytokines from blood with surface immobilized polysaccharides
US11123466B2 (en) 2009-12-01 2021-09-21 Exthera Medical Corporation Methods for removing cytokines from blood with surface immobilized polysaccharides
US10537280B2 (en) 2011-02-15 2020-01-21 Exthera Medical Corporation Device and method for removal of blood-borne pathogens, toxins and inflammatory cytokines
US11266772B2 (en) 2012-06-13 2022-03-08 Exthera Medical Corporation Use of heparin and carbohydrates to treat cancer
US10639413B2 (en) 2013-06-24 2020-05-05 Exthera Medical Corporation Blood filtration system containing mannose coated substrate
US10487350B2 (en) 2013-11-08 2019-11-26 Exthera Medical Corporation Methods for diagnosing infectious diseases using adsorption media
US10457974B2 (en) 2013-11-08 2019-10-29 Exthera Medical Corporation Methods for diagnosing infectious diseases using adsorption media
US11306346B2 (en) 2013-11-08 2022-04-19 Exthera Medical Corporation Methods for diagnosing infectious diseases using adsorption media
US11844895B2 (en) 2014-04-24 2023-12-19 Exthera Medical Corporation Method for removing bacteria from blood using high flow rate
US10857283B2 (en) 2014-09-22 2020-12-08 Exthera Medical Corporation Wearable hemoperfusion device
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
US10786615B2 (en) 2016-03-02 2020-09-29 Exthera Medical Corporation Method for treating drug intoxication
US11911551B2 (en) 2016-03-02 2024-02-27 Exthera Medical Corporation Method for treating drug intoxication
US20220054725A1 (en) * 2019-11-19 2022-02-24 Immunicom, Inc. System and method for removal of immune inhibitors from biological fluids
CN114650852A (en) * 2019-11-19 2022-06-21 英谬免疫股份有限公司 System and method for removing immunosuppressive agents from biological fluids
US20220054726A1 (en) * 2019-11-19 2022-02-24 Immunicom, Inc. System and method for removal of immune inhibitors from biological fluids

Also Published As

Publication number Publication date
US8197430B1 (en) 2012-06-12
US8133490B2 (en) 2012-03-13
US20080057060A1 (en) 2008-03-06

Similar Documents

Publication Publication Date Title
US8133490B2 (en) Method and system to remove cytokine inhibitors in patients
AU2009227872B2 (en) Method and system to remove soluble TNFR1, TNFR2, and IL2 in patients
US6620382B1 (en) Method and compositions for treatment of cancers
JP2006249112A (en) Method and system to remove cytokine inhibitor in patient
CA2490218C (en) Extracorporeal photopheresis in combination with anti-tnf treatment

Legal Events

Date Code Title Description
AS Assignment

Owner name: BIOPHERESIS TECHNOLOGIES, INC., GEORGIA

Free format text: CHANGE OF NAME;ASSIGNOR:BIOPHERESIS TECHNOLOGIES, LLC;REEL/FRAME:017678/0110

Effective date: 20050322

Owner name: BIOPHERESIS TECHNOLOGIES, LLC, TENNESSEE

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:LENTZ, M. RIGDON;REEL/FRAME:017678/0100

Effective date: 20011221

STCB Information on status: application discontinuation

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

AS Assignment

Owner name: INNATUS CORPORATION, CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BIOPHERESIS TECHNOLOGIES, INC.;REEL/FRAME:031754/0411

Effective date: 20130604