CA2013582C - Method for enhancing transmembrane transport of exogenous molecules - Google Patents

Method for enhancing transmembrane transport of exogenous molecules Download PDF

Info

Publication number
CA2013582C
CA2013582C CA002013582A CA2013582A CA2013582C CA 2013582 C CA2013582 C CA 2013582C CA 002013582 A CA002013582 A CA 002013582A CA 2013582 A CA2013582 A CA 2013582A CA 2013582 C CA2013582 C CA 2013582C
Authority
CA
Canada
Prior art keywords
receptor
biotin
folate
exogenous molecule
binding
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.)
Expired - Lifetime
Application number
CA002013582A
Other languages
French (fr)
Other versions
CA2013582A1 (en
Inventor
Mark Alan Horn
Peter Frederick Heinstein
Philip Stewart Low
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.)
Purdue Research Foundation
Original Assignee
Purdue Research Foundation
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
Application filed by Purdue Research Foundation filed Critical Purdue Research Foundation
Publication of CA2013582A1 publication Critical patent/CA2013582A1/en
Application granted granted Critical
Publication of CA2013582C publication Critical patent/CA2013582C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/555—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
    • A61K47/557—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells the modifying agent being biotin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A61K47/551—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/66—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells
    • A61K47/665—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells the pre-targeting system, clearing therapy or rescue therapy involving biotin-(strept) avidin systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/004—Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/64—General methods for preparing the vector, for introducing it into the cell or for selecting the vector-containing host
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/82—Vectors or expression systems specially adapted for eukaryotic hosts for plant cells, e.g. plant artificial chromosomes (PACs)
    • C12N15/8201—Methods for introducing genetic material into plant cells, e.g. DNA, RNA, stable or transient incorporation, tissue culture methods adapted for transformation
    • C12N15/8206—Methods for introducing genetic material into plant cells, e.g. DNA, RNA, stable or transient incorporation, tissue culture methods adapted for transformation by physical or chemical, i.e. non-biological, means, e.g. electroporation, PEG mediated
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids

Abstract

A method is provided for enhancing transmembrane transport of exogenous molecules. The method comprises contacting a membrane of a living cell with a complex formed between said molecules and ligands selected from biotin, biotin analogs and other biotin receptor-binding ligands, and/or folic acid, folate analogs and other folate receptor-binding ligands to initiate receptor mediated transmembrane transport of the ligand complex. The method is used for the efficient delivery of peptides, proteins, nucleic acids and other compounds capable of modifying cell function into plant, animal, yeast, and bacterial cells.

Description

METHOD FOR ENHANCING TRANSMEMBRANE
TRANSPORT OF EXOGENOUS MOLECULES
FIELD OF THE INVENTION
This invention relates to a method for enhancing transmembrane transport of exogenous molecules. More particularly, the use of nutrient receptors, including biotin or folate receptors, and the respective associated receptor mediated endocytotic mechanism associated with such receptors, is utilized to enhance the efficiency of cellular uptake of exogenous molecules capable of modulating or otherwise modifying cell function.

BACKGROUND AND SUMM-ARY OF THE INVENTION
Transmembrane transport of nutrient molecules is a critical cellular function. Because practitioners have recognized the importance of transrnembrane .transport to many areas of medical and biological science, including drug therapy and gene transfer, there has been significant research efforts directed to the understanding and application of such processes. Thus, for example, transmembrane delivery of nucleic acids has been encouraged through the use of protein carriers, antibody carriers, liposomal delivery systems, electroporation, direct injection, cell fusion, viral carriers, osmotic shock, and calcium-phosphate mediated transformation. However, many of those techniques are limited both by the types of cells in which transmembrane transport is enabled and by the conditions of use for successful transmembrane transport of exogenous molecular species. Further, many of these known techniques are limited in the type and size of exogenous molecule that can be transported across a membrane without loss of bioactivity.
One method for transmembrane delivery of exogenous molecules having a wide applicability is based on the mechanism of receptor mediated endocytotic activity. Unlike many other methods, receptor mediated endocytotic activity can be used successfully both in vivo and in vitro. Receptor mediated endocytosis involves the movement of ligands bound to membrane receptors into the interior of an area bounded by the membrane through invagination of the membrane. The process is initiated or activated by the binding of a receptor specific ligand to the receptor. Many receptor mediated endocytotic systems have been characterized, including those recognizing galactose, mannose, mannose 6-phosphate, transferrin, asialoglycoprotein, transcobalamin (vitamin B12), a-2 macroglobulins, insulin,_ and other peptide growth factors such as epidermal growth factor (EGF).
Receptor mediated endocytotic activity has been utilized for delivering exogenous molecules such as proteins and nucleic acids to cells. Generally, a specified ligand is chemically conjugated by covalent, ionic or hydrogen bonding to an exogenous molecule of interest, (i.e., the exogenous compound) forming a conjugate molecule having a moiety (the ligand portion).
that is still recognized in the conjugate by a target receptor. Using this technique the phototoxic protein psoralen has been conjugated to insulin and internalized by the insulin receptor endocytotic pathway (Gasparro, Biochem Biophvs Res Comm. 141(2), pp. 502-509, Dec.
15, 1986); the hepatocyte specific receptor for galactose terminal asialoglycoproteins has been utilized for the hepatocyte-specific transmembrane delivery of asialoorosomucoid-poly-L-lysine non-covalently complexed to a DNA plasmid (Wu, G.Y., J. Biol. Chem., 262(10), pp.
4429-4432, 1987); the cell receptor for epidermal growth factor has been utilized to deliver polynucleotides covalently linked to EGF to the cell interior (Myers, European Patent Application No. 0 273 085 Al, published June 6, 1988); the intestinally situated cellular receptor for the organometallic vitamin B12-intrinsic factor complex has been used to mediate delivery to the circulatory system of a vertebrate host a drug, hormone, bioactive peptide or immunogen complexed with vitamin B12 and delivered to the intestine through oral admininistration (Russell-Jones et al., European patent Application No. 0 220 030 A2, published April 29, 1987); the mannose-6-phosphate receptor has been used to deliver low density lipoproteins to cells (Murray, G. J. and Neville, D.M., Jr., J.Bio.Chem, Vol. 255 (24), pp.
1194-11948, 1980); the cholera toxin binding subunit receptor has been used to deliver insulin to cells lacking insulin receptors (Roth and Maddox, J.Cell.Phys.
Vol. 115, p. 151, 1983); and the human chorionic gonadotropin receptor has been employed to deliver a ricin a-chain coupled to HCG to cells with the appropriate HCG receptor in order to kill the cells (Oeltmann and Heath, J.Biol.Chem, vol. 254, p. 1028 (1979)).
The method of the present invention enhances the transmembrane transport of an exogenous molecule across a membrane having biotin or folate receptors that initiate transmembrane transport of receptor bound species. The method takes advantage of (1) the location and multiplicity of biotin and folate receptors on the membrane surfaces of most cells and (2) the associated receptor mediated transmembrane processes. Performance of the method involves formation of a complex between a ligand selected from biotin or other biotin receptor-binding compounds, and/or folic acid or other folate receptor-binding compounds, and an exogenous molecule. A cell.membrane bearing biotin or folate receptors is contacted with this complex, thereby initiating receptor mediated transmembrane transport of the complex. The complex is allowed to contact the membrane surface bearing the corresponding receptors for a time sufficient to initiate and permit transmembrane transport of the complex. The transmembrane transport of exogenous molecules including proteins and polynucleotides has been promoted in plant, mammalian, and bacterial cells.
In one embodiment of this invention, the target receptor for the method of the present invention is the biotin receptor. Biotin is a necessary cellular nutrient that has been found to be preferentially bound by biotin receptor proteins associated with cellular membranes. Commercially available reagents are used to form a covalent complex between biotin and polynucleotides, proteins, or other desired exogenous molecules. According to one preferred embodiment of the present invention, a biotin/exogenous molecule complex is brought into contact with a membrane having associated biotin receptors for a time sufficient to allow binding of the biotin moiety of the complex to a corresponding biotin receptor in the membrane. This binding triggers the initiation of cellular processes that result in transmembrane transport of the complex.
In an alternate but equally preferred embodiment of this invention, folate receptors are targeted to enhance cellular uptake of exogenous molecules. Folate binding receptors are found in most types of cells, and they have been demonstrated to bind and trigger cellular internalization of folates. Thus, folic acid and other art-recognized folate receptor-binding ligands can be chemically bonded to polynucleotides, proteins, or other desired exogenous molecules using art-recognized coupling techniques to provide a folate receptor-binding complex which is readily endocytosed into living cells. In accordance with this embodiment of the present invention, a folate/exogenous molecule complex is brought into contact with a membrane having associated folate receptors for a time sufficient to allow binding of the folate moiety of the complex to a corresponding folate receptor. Folate receptor-binding triggers the initiation of cellular processes that result in transmembrane transport of the complex.
The methods of this invention are particularly useful for increasing the internalization efficiency (cellular uptake) of exogenous molecules that are normally resistant to cellular internalization.
Proteins and polynucleotides previously recognized as difficult to move across cell membranes can be internalized by a cell through application of the method of the present invention. For example, transformation of target cell lines resulting in expression of a protein product has been accomplished by coupling the desired polynucleotide to either biotin or folates, and contacting the cells with the resulting complex for a time sufficient to promote cellular internalization. In one case, a DNA plasmid containing a gene sequence coding for chloramphenicol acetyltransferase (CAT), was biotinylated and transported into E. coli via a biotin receptor mediated_endocytotic pathway and expressed.
Similar examples of transformation or transfection have been noted for biotin or folate linked nucleic acids in 6400.5-324 mammalian systems, prokaryotic systems, and plants. The use of biotin and folates complexes to enhance cellular uptake of complexed exogenous molecules has been demonstrated in vivo and in vitro.

DETA:ILED DESCRIPTION OF THE INVENTION

Generally, this invention provides a method for enhancing transport of an exogenous molecule across a memb:--ane of a living cell. The method comprises the step of contacting the membrane with the exogenous molecule complexed with a ligand selected from the group consisting of biotin, biotin receptor-binding analogs of biotin, and other biotin receptor-binding ligands, for a time sufficient to permit transmembrane transport of said ligand complex.
In a second embodiment, there is provided a method for enhancing transport of an exogenous molecule across a membrane of a living cell, comprising the step of contacting the rnembrane with the exogenous molecule complexed with a ligand selected from the group consisting of folic acid, folate receptor-binding analogs of folic acid, and other folate receptor-binding ligands, for a time sufficient to perm:_t transmembrane transport of said ligand complex.
According to one aspect of the present invention, there is provided a method for enhancing transport of an exogenous molecule across a membrane of a living cell in vitro, said method comprising the step of contacting the membrane with the exogenous molecule complexed with a ligand selected from biotin or biotin receptor-binding analogs of biotin, folate or folate receptor-binding analogs of folate, thianlin or thiamin receptor-binding analogs of thiamin, and ribof:lavin or riboflavin receptor-binding analogs of ribof:lavin, for a time sufficient to permit transmembrane transport of said ligand complex.

7a According to another aspect of the present inveiltion, there is provided a method of modifying an exogenous molecule to enhance transport of the exogenous molecule across the membrane of a living cell, said method characterized by the step of complexing the exogenous molecule with one or more ligands selected from biotin or biotin receptor-binding analogs of biotin, folate or folate receptor-binding analogs of folate, thiamin or thiamin receptor-binding analogs of thiamin, and riboflavin or riboflavin receptor-binding analogs of riboflavin.
According to still another aspect of the present inverition, there is provided a composition of matter adapted for transport across a membrane of a living cell said composition of matter comprising a complex of an exogenous molecule and a ligand selected from folate or folate receptor-binding analogs of folate, thiamin or thiamin receptor-binding analogs of thiamin, and riboflavin or riboflavin receptor-binding analogs of riboflavin.

According to yet another aspect of the present inverition, there is provided a pharmaceutical formulation comprising a complex adapted for transport across a membrane of a living cell, said complex comprising a pharmaceutically active compound or diagnostic agent and a ligand selected from biotin or biotin receptor-binding analogs of biotin, folate or folate receptor-binding analogs of folate, thiamin or thiamin receptor-binding analogs of thiamin, and riboflavin or riboflavin receptor-binding analogs of riboflavin; and a pharmaceutically acceptable carrier, excipient or diluent.

According to a further aspect of the present invention, there is provided a method for enhancing uptake of an. exogenous molecule by a living cell in vitro, said 7b method comprising the step of contacting the cell with the exogenous molecule complexed with a ligand selected from the group consisting of biotin or biotin receptor-binding analogs of biotin, folate or folate receptor-binding analogs of folate, thiamin or thiamin receptor-binding analogs of thiamin, and riboflavin or riboflavin receptor-binding analogs of riboflavin.

According to yet a further aspect of the present inverition, there is provided use, for enhancing transport of an exogenous molecule across a membrane of a living cell, of a conlposition comprising said exogenous molecule complexed with a ligand selected from biotin or biotin receptor-binding analogs of biotin, folate or folate receptor-binding analogs of folate, thiamin or thiamin receptor-binding analogs of thiamin, and riboflavin or riboflavin receptor-binding analogs of riboflavin.

According to still a further aspect of the present inverition, there is provided use, for enhancing uptake of an exogenous molecule by a living cell, of a composition said exogenous molecule complexed with a ligand selected from the group consisting of biotin or biotin receptor-binding analogs of biotin, folate or folate receptor-binding analogs of folate, thiamin or thiamin receptor-binding analogs of thianlin, and riboflavin or riboflavin receptor-binding analogs of riboflavin.

The method of the present invention is effective in all living cells that have biotin and/or folate receptors associated with their cellular membranes. The membrane can defirie an intracellular volume such as the endoplasmic reticulum or other organelles such as mitochondria, or alternatively, the membrane can define the boundary of the cell.
Living cells which can serve as the target for the method of this invention include prokaryotes and eukaryotes, including yeasts, plant cells and animal cells. The present method can be used to modify cellular function of living cells in vitro, i.e., in cell culture, or in vivo, where the cells form part of or otherwise exist in plant tissue or animal tissue.
Thus the cells can form, for example, the roots, stalks or leaves of growing plants and the present method can be performed on such plant cells in any manner which promotes contact of the exogenous molecule/folate or biotin complex with the targeted cells having the requisite receptors. Alternatively, the target cells can form part of the tissue in an animal. Thus the target cells can include, for example, the cells lining the alimentary canal, such as the oral and pharyngeal mucosa, the cells forming the villi of the small intestine, or the cells lining the large intestine.
Such cells of the alimentary canal can be targeted in accordance with this invention by oral administration of a composition comprising an exogenous molecule complexed with folates or biotin or their receptor-binding analogs. Similarly, cells lining the respiratory system (nasal passages/lungs) of an animal can be targeted by inhalation of the present complexes; dermal/epidermal cells and cells of the vagina and rectum can be targeted by topical application of the present complexes; and cells of internal organs including cells of the placenta and the so-called blood/brain barrier can be targeted particularly by parenteral administration of the present ...~
complexes. Pharmaceutical formulations for therapeutic use in accordance with this invention containing effective amounts of the presently described folate and biotin complexes, in admixture with art-recognized excipients appropriate to the contemplated route of administration are within the scope of this invention.
Since not all natural cell membranes possess biologically active biotin or folate receptors, practice of the method of this invention in vitro on a particular cell line can involve altering or otherwise modifying that cell line first to ensure the presence of biologically active biotin or folate receptors. Thus, the number of biotin or folate receptors on a cell membrane can be increased by growing a ceil line on biotin or folate deficient substrates to promote biotin and folate receptor production, or by expression of an inserted foreign gene for the protein or apoprotein corresponding to the biotin or folate receptor.
The present invention is utilized to enhance the cellular uptake of exogenous molecules, in particular those molecules capable of modulating or otherwise modifying cell function, including pharmaceutically active compounds or diagnostic agents.
Suitable exogenous molecules can include, but are not limited to: peptides, oligopeptides, proteins, apoproteins, glycoproteins, antigens and antibodies thereto, haptens and antibodies thereto, receptors and other membrane proteins, retro-inverso oligopeptides, protein analogs in which at least one non-peptide linkage replaces a peptide linkage, enzymes, coenzymes, enzyme inhibitors, amino acids and their derivatives, hormones, lipids, phospholipids, liposomes; toxins such as aflatoxin, digoxin, zanthotoxin, rubratoxin;
antibiotics such as cephalosporins, penicillin, and erythromycin; analgesics such as aspirin, ibuprofen, and acetaminophen, bronchodilators such theophylline and albuterol; beta-blockers such as propranolol, metoprolol, atenolol, labetolol, timolol, penbutolol, and pindolol; antimicrobial agents such as those described above and ciprofloxacin, cinoxacin, and norfioxacin; antihypertensive agents such as clonidine, methyldopa, prazosin, verapamil, nifedipine, captopril, and enalapril; cardiovascular agents including antiarrhythmics, cardiac glycosides, antianginals and vasodilators; central nervous system agents including stimulants, psychotropics, antimanics, and depressants;
antiviral agents; antihistamines such as chlorpheniramine and brompheniramine; cancer drugs including chemotherapeutic agents; tranquilizers such as diazepam, chordiazepoxide, oxazepam, alprazolam, and triazolam; anti-depressants such as fluoxetine, amitriptyline, nortriptyline, and imipramine; H-2 antagonists such as nizatidine, cimetidine, famotidine, and ranitidine; anticonvulsants; antinauseants;
prostaglandins; muscle relaxants; anti-inflammatory substances; ; stimulants; decongestants; antiemetics;
diuretics; antispasmodics; antiasthmatics;
anti-Parkinson agents; expectorants; cough suppressants;
mucolytics; vitamins; and mineral and nutritional additives. Other molecules include nucleotides;
oligonucleotides; polynucleotides; and their art-recognized and biologically functional analogs and derivatives including, for example; methylated polynucleotides and nucleotide analogs having phosphorothioate linkages; plasmids, cosmids, artificial chromosomes, other nucleic acid vectors; antisense polynucleotides including those substantially complementary to at least one endogenous nucleic acid or those having sequences with a sense opposed to at least portions of selected viral or retroviral genomes;
promoters; enhancers; inhibitors; other ligands for regulating gene transcription and translation, and any other biologically active molecule that can form a complex with biotin or folate, or analogs thereof, by direct conjugation of the exogenous molecule with biotin or biotin analog or folate or folate analog through a hydrogen, ionic, or covalent bonding. Also in accordance with this invention is the use of indirect means for associating the exogenous molecule with biotin or folate, or analogs thereof to form liquid complexes, such as by connection through intermediary linkers, spacer arms, bridging molecules, or liposome entrapment, all of which can act to associate the biotin or biotin analog or folate or folate analog with the exogenous molecule of interest. Both direct and indirect means for associating the ligand and the exogenous molecule must not prevent the binding of the ligand held in association with the exogenous molecule to its respective ligand receptor on the cell membrane for operation of the method of the present invention.
Generally, any manner of forming a complex between an exogenous molecule of interest and a ligand capable of triggering receptor mediated endocytosis can be utilized in accordance with the present invention.
This can include covalent, ionic, or hydrogen bonding of the ligand to the exogenous molecule, either directly or indirectly via a linking group. The complex is typically formed by covalent bonding of the receptor-activating moiety to the exogenous molecule through the formation of amide, ester or imino bonds between acid, aldehyde, hydroxy, amino, or hydrazo groups on the respective components of the complex.
Art-recognized biologically labile covalent linkages such as imino bonds (-C=N-) and so-called "active"
esters having the linkage -COOCH2O- or -COOCH(CH3)0-are preferred, especially where the exogenous molecule is found to have reduced functionality in the complexed form. Hydrogen bonding, e.g., that occurring between complementary strands of nucleic acids, can also be used for complex formation. Thus a biotinylated or folated oligonucleotide complementary to at least a portion of a nucleic acid to be delivered to a cell in accordance with this invention can be hybridized with said nucleic acid and the hybrid (complex) used per this invention to enhance delivery of the nucleic acid into cells.
Because of the ready availability of biotinylating reagents and biotinylating methods suitable for use with peptides, proteins, oligonucleotides, polynucleotides, lipids, phospholipids, carbohydrates, liposomes or other lipid vesicles, lower molecular weight therapeutic agents, bioactive compounds, and carriers for therapeutic agents, biotin is a preferred complex forming ligand for use in carrying out this invention. Generally, the biotin/exogenous molecule complex is formed by covalently binding biotin or a biotin derivative to the exogenous molecule of interest. Transmembrane transport via the biotin/biotin receptor pathway is also preferred because biotin is a necessary nutrient for a wide variety of cells, and biotin receptors that mediate endocytotic activity have been identified in mammalian, plant, and bacterial cells.
Formation of a complex between biotin and an exogenous molecule of interest is readily accomplished.
Biotin and its analogs can be easily conjugated to proteins by activating the carboxyl group of biotin, thereby making it reactive with the free amino groups of the proteins to form a covalent amide linking bond. A
biotinylating reagent such as D-biotin-N-hydroxy-succinimide ester or biotinyl-p-nitrophenyl ester can be used. The activated ester reacts under mild conditions with amino groups to incorporate a biotin residue into the desired molecule.
The procedure to be followed for biotinylating macromolecules using D-biotin-N-hydroxy-succinimide ester is well known in the art (Hofmann et al., J.Am.Chem.Soc. 100, 3585-3590 (1978)). Procedures suitable for biotinylating an exogenous molecule using biotinyl-p-nitrophenyl ester as a biotinylating reagent are also well known in the art (Bodanszk et al., ..r:::r... . ..
, 2013582 J.Am.Chem.Soc. 99, 235 (1977)). Other reagerits such as D-biotinyl-E-aminocaproic acid N-hydroxy-succinimide ester in which E-aminocaproic acid serves as a spacer link to reduce steric hindrance can also be used for the purposes of the present invention.
Oligonucleotides and polynucleotides can also be biotinylated using both indirect and direct methods.
Indirect methods include end-labeling of a polynucleotide with a biotinylated nucleotide, or nick translation that incorporates biotinylated nucleotides.
Nick translation or end labeling of DNA can be accomplished using methods described in Maniatis et al., Molecular Cloning: A Laboratory Manual, pp. 109-116, Cold Spring Harbor Press (1982). Direct methods are those procedures in which biotin is directly attached to a target polynucleotide using a biotinylating reagent.
Photoactivatible reagents such as the acetate salt of N-(4-azido-2-nitrophenyi)-N-(3-biotinylaminopropyl)-N-methyl-l,3-propanediamine (photobiotin) can be used to biotinylate DNA according to the method of Forster et al., Nuc. Acids Res. 13:745-761. An alternative method uses a biotin hydrazide reagent in a bisulfite catalyzed reaction capable of transamination of nucleotide bases such as cytidine according to the method described by Reisfeld et al., B.B.R.C. 142:519-526 (1988). This method simply requires a 24 hour incubation of DNA or RNA with biotin hydrazide at 10mg/ml in an acetate buffer, pH 4.5, containing 1 M bisulfite. Biotin hydrazide can also be used to biotinylate carbohydrates or other exogenous molecules containing a free aldehyde.
Biotin analogs such as biocytin, biotin sulfoxide, oxybiotin and other biotin receptor-binding compounds are liquids that may also be used as suitable complexing agents to promote the transmembrane transport of exogenous molecules in accordance with this invention. Other compounds capable of binding to biotin receptors to initiate receptor mediated endocytotic transport of the complex are also contemplated. Such can include other receptor-binding ligands such as, for example, anti-idiotypic antibodies to the biotin receptor. An exogenous molecule complexed with an anti-idiotypic antibody to a biotin receptor could be used to trigger transmembrane transport of the complex in accordance with the present invention.
Folate receptors that mediate endocytotic activity have previously been identified in bacterial cells (Kumar et al., J. Biol. Chem., 262, 7171-79 (1987)). Folic acid, folinic acid, pteropolyglutamic acid, and folate receptor-binding pteridines such as tetrahydropterins, dihydrofolates, tetrahydrofolates, and their deaza and dideaza analogs are preferred complex-forming ligands used in accordance with a second embodiment of this invention. The terms "deaza" and "dideaza" analogs refers to the art recognized analogs having a carbon atom substituted for one or.two nitrogen atoms in the naturally occuring folic acid structure.
For example, the deaza analogs include the 1-deaza, 3-deaza, 5-deaza, 8-deaza, and 10-deaza analogs. The dideaza analogs include, for example, 1,5 dideaza, 5,10-dideaza, 8,10-dideaza, and 5,8-dideaza analogs.
The foregoing folic acid derivatives are conventionally termed "folates", reflecting their capacity to bind with folate-receptors, and such ligands when complexed with exogenous molecules are effective to enhance transmembrane transport. Other folates useful as complex forming ligands for this invention are the folate receptor-binding analogs aminopterin, amethopterin (methotrexate), N10-methylfolate, 2-deamino-hydroxyfolate, deaza analogs such as 1-deazamethopterin or 3-deazamethopterin, and 3',5'-dichloro-4-amino-4-deoxy-N10-methylpteroylglutamic acid (dichloromethotrexate). Other.suitable ligands capable of binding to folate receptors to initiate receptor mediated endocytotic transport of the complex include anti-idiotypic antibodies to the folate receptor. An exogenous molecule in complex with an anti-idiotypic antibody to a folate receptor is used to trigger transmembrane transport of the complex in accordance with the present invention.
Folated ligands can be complexed with the exogenous molecules hereinbefore defined using art-recognized covalent coupling techniques identical to or closely paralleling those referenced above for the biotinylate ligand complexes. Thus, for example, a carboxylic acid on the folate moiety or on the exogenous molecule can be activated using, for example, carbonyldiimidazole or standard carbodiimide coupling reagents such as 1-ethyl-3-(3-dimethylaminopropyl)carbo-diimide (EDC) and thereafter reacted with the other component of the complex having at least one nucleophilic group, viz hydroxy, amino, hydrazo, or thiol, to form the respective complex coupled through an ester, amide, or thioester bond. Thus complexes can be readily formed between folate ligands and peptides, proteins, nucleic acids, including both RNA and DNA, phosphorodithioate analogs of nucleic acids, oligonucleotides, polynucleotides, lipids and lipid vesicles, phospholipids, carbohydrates and like exogenous molecules capable of modifying cell function.
The ligand complexes enable rapid, efficient delivery of the cell function-modifying moiety through cellular membranes and into the cell.
It is contemplated that both folate and biotinylate-receptor binding ligands can be used advantageously in combination to deliver exogenous molecules through cell membranes. Thus, for example, an exogenous molecule can be multiply conjugated with both folate and biotinylate ligands to enhance opportunity for binding with the respective cell membrane receptors. Alternatively, independent portions of a dose of an exogenous compound can be biotinylated and folate-coupled, respectively, and the portions of the resulting conplexes can subsequently be combined to provide a mixture of ligand complexes for modification of cell function.
Receptor mediated cellular uptake of biotinylated or folate-derivatized polynucleotides provides a convenient, efficient mechanism for transformation of cells. The method is particularly valuable for cell transformation because it is applicable even to cell types, such as plant cells, which are normally resistant to standard transformation techniques. Delivery of foreign genes to the cell cytoplasm can be accomplished with high efficiency using the present invention. Once delivered through the cell membrane to the cell interior, foreign genes can be expressed to produce a desired protein. In addition, other nucleic acids can be introduced, for example, an antisense-RNA sequence capable of binding interference with endogenous messenger RNA.
Artificially generated phospholipid vesicles have been used as carriers for introducing membrane-impermeable substances into cells, as instruments for altering lipid composition of membranes in intact cells, and as inducers of cell fusion.
Liposome/cell membrane interaction is potentiated in accordance with one application of the method of this invention by contacting the cell membrane with a liposome containing the exogenous molecule and bearing ligands on its membrane contacting surface. For example, liposome-forming phospholipids can be biotinylated or folate-conjugated through, for example, headgroup functional groups such as hydroxy and amino groups. The resulting phospholipid/ligand complex is then used itself or in combination with unmodified phospholipids to form liposomes containing exogenous molecules capable of modulating or otherwise modifying cell function. The resulting liposomes, again formed in whole or in part from the phospholipid/biotin or folate complex, present biotin or folate receptor-binding groups to the cell surface, triggering the receptor mediated endocytosis mechanism, thereby promoting delivery of the liposome-contained substances into the cell. One readily available phospholipid that can be used in accordance with the above-described method is phosphatidylethanolamine. That phospholipid can be conveniently complexed using art-recognized procedures with either biotin, biotin analogs or folate-receptor-binding ligands to form a phospholipid/ligand complex. The receptor-binding complex can be combined with other phospholipids, for example, phosphatidylcholine and that mixture can be used to form liposomes containing biologically active substances for delivery of those biologically active substances to cells.
It is further contemplated in accordance with this invention that other cell nutrients for which there exists receptors and associated receptor mediated endocytotic uptake could serve as ligands for forming complexes with exogenous molecules'to enhance their cellular uptake. Among nutrients believed to trigger receptor mediated endocytosis and having application in accordance with the presently disclosed method are niacin, pantothenic acid, riboflavin, thiamin, pyridoxal, and ascorbic acid. These non-organometallic nutrients, and their analogs and derivatives thereof, constitute ligands that can be coupled with exogenous molecules to form ligand complexes for contact with cell membranes following the same procedures described hereinabove for biotin and folate. These foregoing nutrients are generally required nutrients for mammalian cells. Exogenous molecules coupled with the foregoing non-organometallic nutrients can be used to deliver effective amounts of therapeutic agents or pharmaceutically active agents such as previously described through parenteral or oral routes of administration to human or animal hosts.
The following examples are provided to illustrate further the method of the present invention.

Example 1 - RAT PHEOCHROMOCYTOMA CELL UPTAKE OF BIOTIN
CONJUGATED INSULIN:

Rat pheochromocytoma (PC-12) cells were obtained from America Type Culture Collection and were grown (37 C, 5% CO2 in humidified air) attached to plastic flasks for 2 to 3 weeks until confluent in a medium of 85% RMPI 1640, 10% v/v heat inactivated horse serum, and 5% fetal calf serum containing 1%
streptomycin-penicillin.
Biotin and fluorescein labeled insulin was prepared. To 1 ml of a 1 mg/mi solution of insulin protein in phosphate buffered saline was added simultaneously 100 l of a 1 mg/mi solution of fluorescein isothiocyanate (FITC) in dimethylformamide (DMF) and 100 p1 of a 1 mg/mi solution of N-hydroxysuccinimido biotin in dimethylsuifoxide (DMSO). The two labeling reagents were allowed to react at room temperature for 4 hours, after which the unreacted reagents were quenched with 10 ul ethanolamine. The quenched reaction mixture was then dialyzed against double distilled water until unreacted fluorescein derivatives no longer dialyzed into the water. The covalent attachment of biotin and fluorescein to the desired protein was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blot analysis.
As a control, non-biotinylated fluorescein labeled insulin was prepared. 1 ml of a 1 mg/ml solution of insulin was added 0.5 ml of a l mg/ml solution of fluorescein isothiocyanate (FITC) in dimethylformamide (DMF). The reaction was allowed to proceed for 4 hours in the dark at room temperature.
After 4 hours the reaction was quenched with 10 p1 ethanolamine, and the labeled insulin solution was dialyzed against double distilled water until unreacted FITC no longer appeared in the solution.
The rat PC12 cells were grown in modified RMPI
1640 medium as a monolayer on the bottom of a culture flask. Before removing the cells, the monolayer was washed with a 20 ml portion of fresh Locke's solution.
The cells were then displaced into 20 ml of the Locke's solution by gentle agitation with a stream Locke's solution. The suspended cells were pelleted by centrifugation at 10,000 x g for 10 seconds and after resuspending in Locke's solution in separate polycarbonate tubes (40m1/tube) to a final density of 1.14 x 106 cells/mi, the following amounts of proteins were added to the cell suspensions: 40 pg fluorescein-labeled insulin was added to the first tube, and to the control tube was added 40 pg biotin-conjugated insulin labelled with fluorescein.
The tubes were allowed to incubate at 37 C. At intervals of 5, 15 and 33 minutes, 0.5 ml of each cell suspension was removed and pelleted at 10,000 x g for 10 seconds. The cell pellet was washed and repelleted twice in 1 ml Locke's solution and then fixed by addition of 200 }el of a 2% formalin solution in phosphate buffered saline. Thirteen microliters of the fixed cell suspension was then,added to a microscope slide and viewed with the fluorescent microscope to detect internalized proteins. No evidence of internalization was noted for the fluorescein labelled insulin acting as a control. Cellular internalization was indicated for the biotinylated insulin labelled with fluorescein, with the amount internalized increasing with time.

Example 2 RAT PHEOCHROMOCYTOMA CELL UPTAKE OF BIOTIN
CONJUGATED HEMOGLOBIN:
Following the same general procedure set forth in Example 1 hemoglobin was biotinylated, and the biotinylated form was shown to be preferentially internalized by rat pheochromocytoma cells as compared to non-biotinylated hemoglobin.

Example 3 SOYBEAN CELL UPTAKE OF BOVINE SERUM ALBUMIN:
Soybean cell suspension cultures of Glycine max Merr Var Kent were maintained by transferring cells to fresh W-38 growth medium every 7 days.
To 20 ml of a suspension culture of soybean cells was added 10 pg of either fluorescein-labeled (control) or fluorescein and biotin labelled bovine serum albumin. The cells were allowed to incubate for up to 6 hours. At varying time intervals 1 ml of the cell suspension was filtered to remove the growth medium, washed with 50 ml fresh growth medium, and resuspended in 20 ml of the same medium. The cell suspension was then viewed with a fluorescent microscope to determine whether cellular internalization of the labelled bovine serum albumin had occurred. Cellular internalization was indicated only for biotinylated, bovine serum albumin.

Example 4 - SOYBEAN CELL UPTAKE OF INSULIN:
Following the same general procedure set forth in Example 3 insulin was biotinylated, and the biotinylated form of insulin was shown to be preferentially internalized by soybean cells as compared to non-biotinylated insulin.

Example 5 - SOYBEAN CELL UPTAKE OF HEMOGLOBIN:
Following the same general procedure set forth in Example 3 hemoglobin was biotinylated, and the biotinylated form of hemoglobin was shown to be preferentially internalized by soybean cells as compared to non-biotinylated hemoglobin.

Example 6- CARROT CELL UPTAKE OF BOVINE SERUM ALBUMIN:
Carrot cells of wild type origin were established and maintained in MS growth medium supplemented with 0.1 mg/L 2,4-dichlorophenoxyacetic acid. Bovine serum albumin was labelled with fluorescein alone as a control or with fluorescein and biotin following the procedures detailed in Example 3.
The carrot cells were then incubated in the presence of the respective labelled bovine serum albumin for 7 hours. All other conditions were the same as those described in Example 3 above. Cellular internalization was found only in those cells contacted with biotin labelled bovine serum albumin.

Example 7 - CARROT CELL UPTAKE OF INSULIN:
Following the same general procedure set forth in Example 6 insulin was biotinylated, and the biotinylated form was shown to be preferentially internalized by carrot cells as compared to non-biotinylated insulin.

Example 8 - CARROT CELL UPTAKE OF HEMOGLOBIN:
Following the same general procedure set forth in Example 6 hemoglobin was biotinylated, and the biotinylated form was shown to be preferentially internalized by carrot cells as compared to non-biotinylated hemoglobin.
Example 9 - SOYBEAN CELL DEGRADATION OF HEMOGLOBIN:
To determine whether hemoglobin was rapidly degraded following cellular internalization by transmembrane transport, soybean cells were allowed to internalize and metabolize biotinylated hemoglobin for a period of 8 hours under conditions described in Example 5, after which the soybean cells were rapidly homogenized in a sodium dodecyl sulfate solution to disaggregate and denature all protein material. The solubilized polypeptides were separated according to molecular weight by polyacrylamide gel electrophoresis and then electroblotted onto nitrocellulose paper. The positions of the biotin-labeled peptides were then visualized on the nitrocellulose blot by staining with horseradish peroxidase-linked avidin and the colored substrate, p-chloronaphthol. All of the biotin-linked material was found to migrate with an apparent molecular weight of -16,000 daltons, about equal to the molecular weight of the parent globin chains of hemoglobin, indicating no breakdown of the parent globin chains had occurred during the 8 hour incubation period.
Exam,ple 10 - IN VIVO DELIVERY TO MICE OF SOYBEAN TRYPSIN
INHIBITOR:

Soybean trypsin inhibitor (SBTI) (-6 mg) was labeled with radioactive 125I using 8 iodobeads*(Bio Rad) in I mL buffer which was then dialyzed to remove unreacted 125I. After dividing into two equal fractions, one fraction was biotinylated with N-hydroxysuccinimidyl biotin and the other fraction was left as an unmodified control. Mice (-25 g) were then injected with either the biotinylated SBTI or the control SBTI by insertion of a hypodermic syringe containing a 25 gauge needle into the tail vein of the T mouse. After 15 minutes, each mouse was sacrificed and * Trade-mark then perfused with heparin-containing isotonic saline via the direct cardiac influx and efflux method. When the various tissues appeared to be blood-free, the perfusion was terminated and each tissue/organ was removed, weighed, and counted for 125I-SBTI in a gamma counter. Although some radioactivity was detected in the mice treated with non-biotinylated 125I-SBTI, between 4 and 100 times more 125I-SBTI was found in the mice treated with biotinylated SBTI, indicating successful in vivo delivery to murine cellular tissue.
Counts per minute/gram wet weight Tissue Control SBTI Biotin SBTI
Liver 535 1967 Lung 107 2941 Kidney 51.52 8697 Intestine 0 700 Muscle 0 1065 Heart 0 739 Brain 0 267 Example 11 - SOYBEAN CELL UPTAKE OF SALMON SPERM DNA:
Protein free salmon-sperm DNA, either in a highly polymerized form (> 50,000 base pair length) or in a sheared form (< 500 base pair length), was transaminated at the cytosine residues. The transaminated DNA (1 mg) was labeled with fluorescein via the addition of 0.5 mg of fluorescein isothiocyanate (FITC) in dimethylsulfoxide (DMSO). The resulting reaction mixture was divided into two portions and the labeling reaction was quenched in one portion by addition of 10 NL of ethanolamine. This quenched portion served as the non-biotinylated control. The remaining DNA was then covalently labeled with biotin via reaction with 0.5 mg of N-hydroxysuccinirnidyl biotin in DMSO. After purification, the two derivatives (1 ug/mi) were separately incubated with soybean suspension culture cells at room temperature for 6 hours and then the cells were washed with 50 ml fresh growth medium and observed by fluorescence microscopy. Only the biotinylated DNA entered the soybean cells.
Example 12 - E. COLI TRANSFORMATION AND EXPRESSION OF
AMPICILLIN RESISTANT GENE:

Plasmid DNA (pUC8) was biotinylated via nick translation in the presence of biotin-l4-dATP using a commercially available nick translation kit (Bethesda Research Laboratories). The biotinylated DNA and unmodified DNA (1 pg) were added to E. coli strain Cu 1230 that had been made competent by treatment with MgC12 and CaCl2 following-the method of Maniatis et al., Molecular Cloning: A Laboratory Manual, pp.
250-251, Cold Spring Harbor Press (1987). After transformation, the successful transformants were selected by plating cells on LB media which contained 50 pg/ml ampicillin and then incubated overnight at 37 C. Colonies which survived the ampicillin were counted and the transformation efficiency was determined. The number of surviving E. coli colonies was at least 100-fold greater in E. coli transformed with the biotinylated plasmids.

Example 13 - BLOCKADE OF DELIVERY OF BIOTINYLATED
PROTEINS INTO SOYBEAN CELLS BY COMPETITION WITH
UNLIGATED BIOTIN:

Insulin, ribonuclease (RNase) and bovine serum albumin (BAS) were individually biotinylated following the same general procedure set forth in Example 1 above. A sample of each of the biotinylated proteins and an unmodified sample of the same protein (control protein) were radioiodinated according to the following protocol. To 1 mL of a 200 mM phosphate buffer, pH 7.0, containing 3 iodobeads (Pierce Chemical Co.) was added 0.2 mCi [125I]-NaI (carrier-free in 1 n NaOH, Amersham) and the mixture was allowed to incubate for 5 minutes to liberate the active iodine species, according to the supplier's instructions. After activation, 1 mg of desired biotinylated or control protein was added in 0.5 mL of iodination buffer. The iodination was allowed to proceed with stirring for 20 minutes. After the iodination was complete, the product was isolated via gel filtration on a Biogel:*PH-10 column. Typical iodinations of ribonuclease A (Sigma Chemical Co.) yielded a product emitting 2 x 105 cprn/}ig.
Uptake of 125I-Iabeled proteins by soybean suspension culture cells in the early exponential growth phase was then assayed as follows. To each culture was Trade-mark ~
added sufficient 125I-labeled macromolecule toachieve a final concentration of 10 g/mL, and the suspension was incubated at 23 for the desired time. After the desired incubation period, the cells were washed for 5 minutes in growth media rebuffered to pH 8 with 15 mM
glycylglycine to remove surface bound ligand. The cell suspension was then filtered, washed with 200 volumes growth media, and placed in counting vials.
Uptake of biotin-conjugated RNase was rapid, reaching 6 x 106 molecules internalized per cell in the first 3 hours. In contrast, unmodified RNase was not internalized, demonstrating the importance of the , biotin adduct. To further confirm the role of biotin in mediating the delivery of RNase, the cell suspension was treated with 1 mM free biotin directly prior to addition of the biotin-derivatized RNase. Free biotin competitively blocked delivery of the conjugated protein into the soybean cells. Therefore, it can be concluded that the internalization process involves recognition of biotin by a limited number of receptors on the plant cell surface.
Similar studies with biotin-labeled BSA and insulin yielded virtually identical results.

Example 14 - PARTIAL PURIFICATION OF BOVINE SERUM
ALBUMIN FOLLOWING ITS INTERNALIZATION BY CULTURED
SOYBEAN CELLS:

Radiolabeled, biotinylated bovine serum albumin was allowed to bind and enter cultured soybean cells following the same.general procedure set forth in Example 13, after which the cells were thoroughly washed, homogenized and extracted to remove cytoplasmic soluble proteins. This cytoplasmic protein extract was separated using standard chromatographic techniques on a Sephadex G-25 gel filtration column to determine whether any small molecular weight fragments might be generated during the co-delivery process. Comparison of the elution profile of the 125I-labeled material isolated from the cell extract with the profile of unmodified 125I-serum albumin showed that the majority of the internalized protein remained intact throughout the 2 hour duration of the internalization study.

Example 15 - RESTORATION OF GROWTH IN CULTURED CELLS
DEFICIENT IN HYPOXANTHINE-GUANINE PHOSPHORIBOSYL
TRANSFERASE (HGPRT) UPON ADDITION OF BIOTINYLATED -HGPRT.

Cells deficient in HGPRT (i.e., the defect in Lesch-Nyhan Syndrome) are able to grow only in a cellular growth medium containing hypoxanthine, aminopterin and thymidine, (HAT), supplemented with purines. However, these same cells were found to grow normally in HAT medium after internalization of biotin-linked HGPRT via the biotin-mediated endocytosis pathway. HGPRT was biotinylated in the presence of hypoxanthine and phosphoribosyl pyrophosphate (to protect the active site) with N-hydroxysuccinimido biotin. The crosslinked enzyme retained 55% of the original activity and SDS PAGE analysis followed by transblotting and avidin-peroxidase binding indicated that a 1-4 biotins were attached per molecules of HGPRT. HGPRT deficient fibroblasts (GM 00152) incubated with biotinylated HGPRT (4.6 x 104 units/cell) grew at a rate comparable to cells supplemented with purines for at least 24 hours. Appropriate control incubations did not grow on HAT medium supplemented with HGPRT, biotin, phosphoribosyl, and inosine monophosphate.

Example 16 - TRANSFORMATION OF CULTURED SOYBEAN CELLS
WITH A KANAMYCIN RESISTANCE GENE USING THE BIOTIN
DELIVERY.SYSTEM:

The expression vector pGA642-643 containing a bacterial kanamycin resistance gene was nicked with EcoRl and the sticky ends were filled in using biotinylated ATP and a T4 polymerase-based nick translation kit following the general procedure set forth in Example 12. Identical control plasmids were left unmodified. Then, to 40 ml of a soybean cell suspension was added either the biotinylated plasmid or the control (nonbiotinylated) plasmid. After incubation for 10 hours, the cells from each flask were transferred to fresh growth medium containing 100 }tg/ml kanamycin and allowed to proliferate under normal conditions.
Each flask was also transferred to fresh medium containing 100 pg/ml kanamycin every 3 days. By day 10, the flask treated with the biotinylated plasmid had increased - 6-fold in cell mass, while the flask treated with the control plasmid exhibited no measurable growth.
Example 17 - USE OF FOLIC ACID CONJUGATION TO DELIVER
RIBONUCLEASE INTO CULTURED HUMAN CELLS:

Activated folic acid was prepared by dissolving 1 mg of folic acid and 3.8 equivalents of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) in 0.5 ml of dimethylsulfoxide (DMSO). The solution was allowed to set for 2.5 hours. A sample of folate-labeled bovine ribonuclease was prepared by treating the ribonuclease with - 34-fold molar excess of EDC-activated folate.
The resulting derivatized RNase contained 12-14 covalently bound folates per protein molecule. A second sample of the ribonuclease was left unmodified to serve as a control. The folate-labeled sample and the control sample were radioiodinated following the same general procedure set forth in Example 13. Following exhaustive dialysis, the two 125I-labeled samples were added to KB cells (a human nasopharyngeal cell line) and examined for uptake of 125I-RNase after 30 minutes. No protein-uptake was seen for RNase control samples, while 107 molecules per cell were internalized by the RNase labeled with folate (RNase-Folate). To confirm that the uptake was indeed folate-mediated, the KB cells were treated with either control RNase or folate-labeled RNase in the presence of a 100-fold molar excess of unliganted folate (100X). The control RNase again displayed no internalization; uptake of the RNase-Folate conjugate was reduced - 7-fold by competitive inhibition. Similar studies yielded corresponding results using hurnan HeLa cells.

; 2013582 Example 18 - USE OF FOLIC ACID CONJUGATION TO DELIVER
SOYBEAN TRYPSIN INHIBITOR (SBTI) INTO CULTURED HUMAN
CELLS:

Experiments following the general procedure set forth in Example 17, with soybean trypsin inhibitor being substituted for ribonuclease, were conducted with virtually identical results. Folate ligation was again demonstrated to be essential for uptake of SBTI by KB
cells.

Example 19 - VISUALIZATION OF RIBONUCLEASE ENDOCYTOSIS
BY KB CELLS USING A CONFOCAL MICROSCOPE:

Bovine ribonuclease (RNase) was labeled with fluorescein isothiocyanate.following the same general procedure set forth in Example 1 and then further labeled with foiate following the same general procedure set forth in Example 17. RNase labeled only with fluoroscein was used as a control. Following extensive dialysis against growth medium, the control and folate-labeled RNase samples were added to separate cultures of KB cells. After 60 minute incubation, the cells were thoroughly washed and examined for uptake.
Only the folate-labeled samples displayed any internal fluorescence when viewed with laser excitation under the confocal microscope (Bio Rad). Furthermore, using the confocal's capability of focusing on a single horizontal plane in each cultured cell, it was readily evident that vesicles filled with the fluorescent-labeled, folate-bound ribonuclease were forming on all regions of the cell surface, pinching off via endocytosis into the interior, and entering the cytoplasm. The vesicles, measuring 0.8 to 1.0 pm across, were easily large enough to accommodate large biomolecules such as proteins and DNA plasmids.
Example 20 - UPTAKE OF RIBONUCLEASE IN COMPLEX WITH
FOLATE BY WHITE BLOOD CELLS:

Fluorescein-labeled RNase was either conjugated to folate or left unmodified (control) following the same general procedure set forth in Example 19. The folate-conjugated and control samples were then.added to freshly drawn whole human blood, incubated at 37 C for 2 hours and then washed thoroughly and examined under the fluorescence microscope. Cells bearing folate receptors that were brought into contact with the RNase/folate/fluorescein complex were found to fluoresce. None of the control cells exhibited fluorescense.

Example 21 - IN VIVO DELIVERY OF RIBONUCLEASE THROUGHOUT
TISSUES OF LIVE MICE FOLLOWING INTRAVENOUS INJECTION:
Ribonuclease was labeled with 125I following the same general procedure set forth in Example 13 and then further conjugated with folate or left unmodified to serve as a control, following the general procedure set forth in Example 17. Live mice were injected with either the folate-conjugated or control sample by inserting a 27 gauge needle into the tail vein of the mice and injecting 0.2 ml of the appropriate sample dissolved in physiological saline. After 1 hour, the mice were anesthetized, perfused with saline and dissected to determine the specific radioactivity of each organ, following the general procedure set forth in Example 10. Uptake was determined by relative comparison of specific radioactivity of the various tissues examined (units compared were counts per minute/gram of tissue divided by the specific activity of a blood sample drawn 3 minutes after injection, i.e., in order to normalize for any variability in the amount injected). Folate conjugation provided greatly enhanced uptake by the liver and lung, while the kidney, an organ responsible for clearance of unwanted proteins, was enriched in unmodified RNase.
Similar results were obtained when the mice were allowed to live for 18 hours post-injection, with preferential uptake of folate-conjugated RNase also being noted in the intestine, heart, muscle and brain.
Example 22 - IN VIVO DELIVERY OF RIBONUCLEASE THROUGHOUT
TISSUES OF LIVE MICE FOLLOWING INTRAPERITONEAL INJECTION:
Folate-derivatized and control RNase (125I-labeled) were prepared as described in Example 21 and injected into the peritoneal cavity of 30g mice using a 27 gauge needle and syringe. After 17 hours, the mice were anesthetized, perfused, and dissected to remove various body tissues. Each tissue was then weighted and counted for radioactivity. The specific uptake of both the control and folate-conjugated RNase were compared following the general procedure set forth in Example 21. As compared to intravenous administration, intraperitoneal injection resulted in enhanced delivery of the folate-derivatized RNase to all tissues except the kidney. Transmembrane delivery across the blood/brain barrier was demonstrated by the brain tissue's preferential uptake of the folate-labeled protein. Similar results were obtained in two other repetitions of the foregoing procedure.

Example 23 - REVERSION OF src-TRANSFORMED FIBROBLASTS TO
DIFFERENTIATED STATE UPON TREATMENT WITH ANTI-SENSE DNA
CONJUGATED TO FOLATE:

A pentadecameric oligonucleotide DNA probe of the formula II
5'-CTTGCTACTCCCAT-O-P-O-(CH2)8-NH3 +

complementary to a sequence spanning the initiation codon of the Rous sarcoma src oncogene and containing a free 3' amino group was derivatized with folate using carbodiimide chemistry. A second sample was left unmodified as a control. Both samples were dissolved in phosphate buffered saline and introduced into culture dishes containing fibroblasts transformed by the Rous sarcoma virus (XC cells) at a final oligonucleotide concentration of 8 x 10-6 M. After 24 hours, the cultured cells were viewed under a microscope. Results showed that ~ 40% of the cells treated with the folate/antisense oligonucleotide complex had reverted to the normal fibroblast-like morphology, while only -10% of the controls displayed the same nontransformed phenotype. The remaining cells in both culture dishes retained their highly rounded shape characteristic of the neoplastic state.

Claims (41)

1. A method for enhancing transport of an exogenous molecule across a membrane of a living cell in vitro, said method comprising the step of contacting the membrane with the exogenous molecule complexed with a ligand selected from biotin or biotin receptor-binding analogs of biotin, folate or folate receptor-binding analogs of folate, thiamin or thiamin receptor-binding analogs of thiamin, and riboflavin or riboflavin receptor-binding analogs of riboflavin, for a time sufficient to permit transmembrane transport of said ligand complex.
2. The method of claim 1 wherein the living cell is a eukaryote.
3. The method of claim 2 wherein the living cell is a plant cell.
4. The method of claim 2 wherein the living cell is an animal cell.
5. The method of claim 2 wherein the living cell is a human cell.
6. The method of claim 1 wherein the living cell is a prokaryote.
7. The method of claim 1 wherein the exogenous molecule is a biologically active compound or a diagnostic agent.
8. The method of claim 1 wherein the exogenous molecule is selected from proteins, oligopeptides, polypeptides, phospholipids, lipids, nucleic acids, and biologically functional analogs of any of said proteins, oligopeptides, polypeptides, phospholipids, lipids, and nucleic acids.
9. The method of claim 8 wherein the exogenous molecule is a nucleic acid or analog thereof.
10. The method of claim 1 wherein the exogenous molecule is contained in a liposome, said liposome comprising liposome-forming phospholipids, at least a portion of which liposome-forming phospholipids are covalently bound through their headgroups to the ligand.
11. A method of modifying an exogenous molecule to enhance transport of the exogenous molecule across the membrane of a living cell, said method characterized by the step of complexing the exogenous molecule with one or more ligands selected from biotin or biotin receptor-binding analogs of biotin, folate or folate receptor-binding analogs of folate, thiamin or thiamin receptor-binding analogs of thiamin, and riboflavin or riboflavin receptor-binding analogs of riboflavin.
12. The method of claim 11 wherein the exogenous molecule is that of a pharmaceutically active compound or diagnostic agent.
13. The method of claim 11 wherein the exogenous molecule is a protein, an oligopeptide, a polypeptide, a lipid, a phospholipid, a nucleic acid or a biologically functional analog of any one of said oligopeptide, polypeptide, lipid, phospholipid, and nucleic acid.
14. The method of claim 13 wherein the exogenous molecule is a nucleic acid or analog thereof.
15. A composition of matter adapted for transport across a membrane of a living cell said composition of matter comprising a complex of an exogenous molecule and a ligand selected from folate or folate receptor-binding analogs of folate, thiamin or thiamin receptor-binding analogs of thiamin, and riboflavin or riboflavin receptor-binding analogs of riboflavin.
16. The composition of matter of claim 15 wherein the exogenous molecule is that of a pharmaceutically active compound or diagnostic agent and wherein the complex is formed by covalently binding the ligand and the molecule directly or indirectly through a linking group.
17. The composition of matter of claim 15 wherein the exogenous molecule is that of a pharmaceutically active compound or diagnostic agent and wherein the complex is formed as a liposome containing the exogenous molecule, said liposome bearing the ligand on its surface.
18. The composition of matter of claim 15 wherein the exogenous molecule is that of a protein, an oligopeptide, a polypeptide, a lipid, a phospholipid, a nucleic acid or a biologically functional analog of any one of said protein, oligopeptide, polypeptide, lipid, phospholipid and nucleic acid.
19. The composition of matter of claim 18 wherein the complex is formed by covalent, ionic or hydrogen bonding of the ligand to the exogenous molecule either directly or indirectly through a linking group.
20. The composition of matter of claim 18 formed as a liposome containing the exogenous molecule said liposome bearing the ligand on its surface.
21. The composition of matter of claim 15 wherein the exogenous molecule is a phospholipid and the ligand is covalently bound to the headgroup of the phospholipid directly or indirectly through a linking group.
22. A pharmaceutical formulation comprising a complex adapted for transport across a membrane of a living cell, said complex comprising a pharmaceutically active compound or diagnostic agent and a ligand selected from biotin or biotin receptor-binding analogs of biotin, folate or folate receptor-binding analogs of folate, thiamin or thiamin receptor-binding analogs of thiamin, and riboflavin or riboflavin receptor-binding analogs of riboflavin; and a pharmaceutically acceptable carrier, excipient or diluent.
23. The formulation of claim 22 wherein the ligand is biotin, a biotin receptor-binding analog of biotin, or other biotin receptor-binding ligand.
24. The formulation of claim 22 wherein the ligand is folate, a folate receptor-binding analog of folate, or other folate receptor-binding ligand.
25. The formulation of claim 22 wherein the complex is formed by covalently binding the ligand and the compound or agent directly or indirectly through a linking group.
26. The formulation of claim 22 wherein the complex is formed as a liposome containing the compound or agent, said liposome bearing the ligand on its exterior surface.
27. The formulation of claim 22 wherein the pharmaceutically active compound or diagnostic agent comprises a protein, an oligopeptide, a polypeptide, a nucleic acid or a biologically functional analog of any one of said protein, oligopeptide, polypeptide, and nucleic acid.
28. The formulation of claim 27 wherein the complex is formed by covalent, ionic or hydrogen bonding of the ligand to the pharmaceutically active compound or diagnostic agent, either directly or indirectly through a linking group.
29. The formulation of claim 27 wherein the complex is formed as a liposome containing the pharmaceutically active compound or diagnostic agent, said liposome bearing the ligand on its exterior surface.
30. A method for enhancing uptake of an exogenous molecule by a living cell in vitro, said method comprising the step of contacting the cell with the exogenous molecule complexed with a ligand selected from the group consisting of biotin or biotin receptor-binding analogs of biotin, folate or folate receptor-binding analogs of folate, thiamin or thiamin receptor-binding analogs of thiamin, and riboflavin or riboflavin receptor-binding analogs of riboflavin.
31. Use, for enhancing transport of an exogenous molecule across a membrane of a living cell, of a composition comprising said exogenous molecule complexed with a ligand selected from biotin or biotin receptor-binding analogs of biotin, folate or folate receptor-binding analogs of folate, thiamin or thiamin receptor-binding analogs of thiamin, and riboflavin or riboflavin receptor-binding analogs of riboflavin.
32. The use of claim 31 wherein the living cell is a eukaryote.
33. The use of claim 32 wherein the living cell is a plant cell.
34. The use of claim 32 wherein the living cell is an animal cell.
35. The use of claim 32 wherein the living cell is a human cell.
36. The use of claim 31 wherein the living cell is a prokaryote.
37. The use of claim 31 wherein the exogenous molecule is a biologically active compound or a diagnostic agent.
38. The use of claim 31 wherein the exogenous molecule is selected from proteins, oligopeptides, polypeptides, phospholipids, lipids, nucleic acids, or biologically functional analogs thereof.
39. The use of claim 38 wherein the exogenous molecule is a nucleic acid or analog thereof.
40. The use of claim 31 wherein the exogenous molecule is contained in a liposome, said liposome comprising liposome-forming phospholipids, at least a portion of which are covalently bound through their headgroups to the ligand.
41. Use, for enhancing uptake of an exogenous molecule by a living cell, of a composition comprising said exogenous molecule complexed with a ligand selected from the group consisting of biotin or biotin receptor-binding analogs of biotin, folate or folate receptor-binding analogs of folate, thiamin or thiamin receptor-binding analogs of thiamin, and riboflavin or riboflavin receptor-binding analogs of riboflavin.
CA002013582A 1989-04-03 1990-04-02 Method for enhancing transmembrane transport of exogenous molecules Expired - Lifetime CA2013582C (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US33181689A 1989-04-03 1989-04-03
US331,816 1989-04-03
US498,762 1990-03-28
US07/498,762 US5108921A (en) 1989-04-03 1990-03-28 Method for enhanced transmembrane transport of exogenous molecules

Publications (2)

Publication Number Publication Date
CA2013582A1 CA2013582A1 (en) 1990-10-03
CA2013582C true CA2013582C (en) 2007-06-19

Family

ID=26987937

Family Applications (2)

Application Number Title Priority Date Filing Date
CA002013582A Expired - Lifetime CA2013582C (en) 1989-04-03 1990-04-02 Method for enhancing transmembrane transport of exogenous molecules
CA002013580A Abandoned CA2013580A1 (en) 1989-04-03 1990-04-02 Method for enhancing transmembrane transport of exogenous molecules

Family Applications After (1)

Application Number Title Priority Date Filing Date
CA002013580A Abandoned CA2013580A1 (en) 1989-04-03 1990-04-02 Method for enhancing transmembrane transport of exogenous molecules

Country Status (13)

Country Link
US (4) US5108921A (en)
EP (1) EP0466816B1 (en)
JP (1) JP3232347B2 (en)
AT (1) ATE160583T1 (en)
AU (1) AU5437590A (en)
CA (2) CA2013582C (en)
DE (1) DE69031763T2 (en)
DK (1) DK0466816T3 (en)
ES (1) ES2113346T3 (en)
IE (1) IE81171B1 (en)
IL (1) IL93983A (en)
PT (1) PT93646A (en)
WO (1) WO1990012096A1 (en)

Families Citing this family (865)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5550111A (en) * 1984-07-11 1996-08-27 Temple University-Of The Commonwealth System Of Higher Education Dual action 2',5'-oligoadenylate antiviral derivatives and uses thereof
US5643889A (en) * 1984-07-11 1997-07-01 Temple University-Of The Commonwealth System Of Pennsylvania Cholesterol conjugates of 2'5'-oligoadenylate derivatives and antiviral uses thereof
US5688488A (en) * 1989-04-03 1997-11-18 Purdue Research Foundation Composition and method for tumor imaging
US5108921A (en) * 1989-04-03 1992-04-28 Purdue Research Foundation Method for enhanced transmembrane transport of exogenous molecules
US6114513A (en) * 1990-01-11 2000-09-05 Isis Pharmaceuticals, Inc. Thiol-derivatized oligonucleotides
US6153737A (en) * 1990-01-11 2000-11-28 Isis Pharmaceuticals, Inc. Derivatized oligonucleotides having improved uptake and other properties
US7037646B1 (en) 1990-01-11 2006-05-02 Isis Pharmaceuticals, Inc. Amine-derivatized nucleosides and oligonucleosides
US6753423B1 (en) 1990-01-11 2004-06-22 Isis Pharmaceuticals, Inc. Compositions and methods for enhanced biostability and altered biodistribution of oligonucleotides in mammals
US6395492B1 (en) * 1990-01-11 2002-05-28 Isis Pharmaceuticals, Inc. Derivatized oligonucleotides having improved uptake and other properties
US20040142899A1 (en) * 1990-01-11 2004-07-22 Isis Pharmaceuticals, Inc. Compositions and methods for enhanced biostability and altered biodistribution of oligonucleotides in mammals
CA2103371C (en) * 1991-06-05 2003-09-16 George Y. Wu Targeted delivery of genes encoding secretory proteins
US6287792B1 (en) * 1991-06-17 2001-09-11 The Regents Of The University Of California Drug delivery of antisense oligonucleotides and peptides to tissues in vivo and to cells using avidin-biotin technology
US5254342A (en) * 1991-09-30 1993-10-19 University Of Southern California Compositions and methods for enhanced transepithelial and transendothelial transport or active agents
US5981273A (en) * 1991-09-30 1999-11-09 Boehringer Ingelheim Int'l. Gmbh Composition comprising an endosomolytic agent for introducing nucleic acid complexes into higher eucaryotic cells
NZ244306A (en) * 1991-09-30 1995-07-26 Boehringer Ingelheim Int Composition for introducing nucleic acid complexes into eucaryotic cells, complex containing nucleic acid and endosomolytic agent, peptide with endosomolytic domain and nucleic acid binding domain and preparation
US6831166B2 (en) 1992-10-23 2004-12-14 Isis Pharmaceuticals, Inc. Derivatized oligonucleotides having improved uptake and other properties
US6335434B1 (en) 1998-06-16 2002-01-01 Isis Pharmaceuticals, Inc., Nucleosidic and non-nucleosidic folate conjugates
CA2131620A1 (en) * 1992-03-20 1993-09-30 Louis C. Smith A dna transporter system and method of use
US6033884A (en) * 1992-03-20 2000-03-07 Baylor College Of Medicine Nucleic acid transporter systems and methods of use
WO1994004194A1 (en) * 1992-08-14 1994-03-03 Massachusetts Institute Of Technology Nucleic acid recognition and transport
US20020173474A1 (en) * 1993-02-12 2002-11-21 President And Fellows Of Harvard College Methods & materials involving dimerization-mediated regulation of biological events
US5993860A (en) * 1993-06-17 1999-11-30 Venture Lending NSADI delivery employing a powdered hydrocolloid gum obtainable from higher plants
US6653458B1 (en) 1993-09-03 2003-11-25 Isis Pharmaceuticals, Inc. Modified oligonucleotides
EP0728139B1 (en) 1993-09-03 2003-08-13 Isis Pharmaceuticals, Inc. Amine-derivatized nucleosides and oligonucleosides
US5635385A (en) * 1993-09-15 1997-06-03 Temple University-Of The Commonwealth System Of Higher Education Multi-unit ribozyme inhibition of oncogene gene expression
ES2316148T3 (en) * 1994-03-23 2009-04-01 Ohio University COMPACTED NUCLEIC ACIDS AND ITS SUPPLY TO CELLS.
US6077835A (en) * 1994-03-23 2000-06-20 Case Western Reserve University Delivery of compacted nucleic acid to cells
US5972901A (en) * 1994-03-23 1999-10-26 Case Western Reserve University Serpin enzyme complex receptor--mediated gene transfer
US5844107A (en) * 1994-03-23 1998-12-01 Case Western Reserve University Compacted nucleic acids and their delivery to cells
US5837523A (en) * 1994-05-05 1998-11-17 The Trustees Of The University Of Pennsylvania Compositions and methods of treating tumors
US5670347A (en) 1994-05-11 1997-09-23 Amba Biosciences Llc Peptide-mediated gene transfer
US5716594A (en) * 1994-06-06 1998-02-10 The Jmde Trust Biotin compounds for targetting tumors and sites of infection
ATE268186T1 (en) * 1994-06-06 2004-06-15 Thejmde Trust BIOTIN COMPOUNDS TO TARGE TUMORS AND SIGNS OF INFECTION
US5837533A (en) * 1994-09-28 1998-11-17 American Home Products Corporation Complexes comprising a nucleic acid bound to a cationic polyamine having an endosome disruption agent
AU8122094A (en) * 1994-10-19 1996-05-15 Human Genome Sciences, Inc. Human hypoxanthine-(guanine) phosphoribosyl transferase-2
IL114615A0 (en) 1995-07-16 1995-11-27 Yeda Res & Dev Modulators of the function of fas receptors and other proteins
AU5259796A (en) 1995-02-10 1996-08-27 Worcester Foundation For Biomedical Research, Inc. Delivery of exogenous compounds
US5846743A (en) * 1995-02-22 1998-12-08 Brigham And Women's Hospital, Inc. Polyphoshoinositide binding peptides for intracellular drug delivery
US5674748A (en) * 1995-03-14 1997-10-07 Thomas Jefferson University Human cyclin-dependent kinase-like proteins and methods of using the same
US5547668A (en) * 1995-05-05 1996-08-20 The Board Of Trustees Of The University Of Illinois Conjugates of folate anti-effector cell antibodies
US5672500A (en) * 1995-05-18 1997-09-30 Thomas Jefferson University Mch2, an apoptotic cysteine protease, and compositions for making and methods of using the same
US6420549B1 (en) 1995-06-06 2002-07-16 Isis Pharmaceuticals, Inc. Oligonucleotide analogs having modified dimers
US5817789A (en) * 1995-06-06 1998-10-06 Transkaryotic Therapies, Inc. Chimeric proteins for use in transport of a selected substance into cells
WO1997007827A1 (en) * 1995-08-22 1997-03-06 Thomas Jefferson University Gab1, A Grb2 BINDING PROTEIN, AND COMPOSITIONS FOR MAKING AND METHODS OF USING THE SAME
US20030119724A1 (en) * 1995-11-22 2003-06-26 Ts`O Paul O.P. Ligands to enhance cellular uptake of biomolecules
CA2190304A1 (en) * 1995-12-15 1997-06-16 Elazar Rabbani Property effecting and/or property exhibiting compositions for therapeutic and diagnostic uses
US5789244A (en) * 1996-01-08 1998-08-04 Canji, Inc. Compositions and methods for the treatment of cancer using recombinant viral vector delivery systems
US6392069B2 (en) 1996-01-08 2002-05-21 Canji, Inc. Compositions for enhancing delivery of nucleic acids to cells
US6344436B1 (en) 1996-01-08 2002-02-05 Baylor College Of Medicine Lipophilic peptides for macromolecule delivery
US7002027B1 (en) 1996-01-08 2006-02-21 Canji, Inc. Compositions and methods for therapeutic use
US20040014709A1 (en) * 1996-01-08 2004-01-22 Canji, Inc. Methods and compositions for interferon therapy
US6180767B1 (en) 1996-01-11 2001-01-30 Thomas Jefferson University Peptide nucleic acid conjugates
US6060587A (en) 1996-01-29 2000-05-09 The Trustees Of The University Of Pennsylvania Cellular receptor for HIV-1 VPR essential for G2/M phase transition of the cell cycle
US5783566A (en) * 1996-05-10 1998-07-21 California Institute Of Technology Method for increasing or decreasing transfection efficiency
CA2174803C (en) * 1996-04-23 2000-07-11 Jonathan P. Wong Use of liposome encapsulated ciprofloxacin as an immunotherapeutic drug
US6261787B1 (en) 1996-06-03 2001-07-17 Case Western Reserve University Bifunctional molecules for delivery of therapeutics
WO2001008708A2 (en) * 1999-07-29 2001-02-08 Case Western Reserve University Enhanced delivery via serpin enzyme complex receptor ligands
US6072041A (en) * 1996-06-03 2000-06-06 Case Western Reserve University Fusion proteins for protein delivery
US6310052B1 (en) 1996-06-04 2001-10-30 Queen's University At Kingston Nitrate esters and their use for neurological conditions
JPH09324000A (en) * 1996-06-05 1997-12-16 Suntory Ltd Zygote of factor specifically recognizing interleukin2 receptor with ribonuclease
US7812149B2 (en) 1996-06-06 2010-10-12 Isis Pharmaceuticals, Inc. 2′-Fluoro substituted oligomeric compounds and compositions for use in gene modulations
US20050119470A1 (en) * 1996-06-06 2005-06-02 Muthiah Manoharan Conjugated oligomeric compounds and their use in gene modulation
US20070275921A1 (en) * 1996-06-06 2007-11-29 Isis Pharmaceuticals, Inc. Oligomeric Compounds That Facilitate Risc Loading
US20050042647A1 (en) * 1996-06-06 2005-02-24 Baker Brenda F. Phosphorous-linked oligomeric compounds and their use in gene modulation
US9096636B2 (en) 1996-06-06 2015-08-04 Isis Pharmaceuticals, Inc. Chimeric oligomeric compounds and their use in gene modulation
US5898031A (en) 1996-06-06 1999-04-27 Isis Pharmaceuticals, Inc. Oligoribonucleotides for cleaving RNA
US20040171031A1 (en) * 1996-06-06 2004-09-02 Baker Brenda F. Sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation
US5980898A (en) 1996-11-14 1999-11-09 The United States Of America As Represented By The U.S. Army Medical Research & Material Command Adjuvant for transcutaneous immunization
US20060002949A1 (en) 1996-11-14 2006-01-05 Army Govt. Of The Usa, As Rep. By Secretary Of The Office Of The Command Judge Advocate, Hq Usamrmc. Transcutaneous immunization without heterologous adjuvant
WO1998020887A1 (en) * 1996-11-14 1998-05-22 Brigham And Women's Hospital, Inc. Polyphosphoinositide binding peptides for intracellular drug delivery
US6797276B1 (en) 1996-11-14 2004-09-28 The United States Of America As Represented By The Secretary Of The Army Use of penetration enhancers and barrier disruption agents to enhance the transcutaneous immune response
US20060002959A1 (en) * 1996-11-14 2006-01-05 Government Of The United States Skin-sctive adjuvants for transcutaneous immuization
WO1998030229A1 (en) 1997-01-10 1998-07-16 Massachusetts Institute Of Technology TREATMENTS FOR NEUROTOXICITY IN ALZHEIMER'S DISEASE BY β-AMYLOID PEPTIDES
US6942963B1 (en) 1997-01-10 2005-09-13 Massachusetts Institute Of Technology Methods for identifying treatments for neurotoxicity in Alzheimer's disease caused by β-amyloid peptides
AU743827B2 (en) 1997-04-09 2002-02-07 Intellect Neurosciences, Inc. Recombinant antibodies specific for beta-amyloid ends, DNA encoding and methods of use thereof
US6716625B1 (en) 1997-04-16 2004-04-06 Claude Selitrennikoff Histidine kinases of Aspergillus and other fungal species, related compositions, and methods of use
US6037461A (en) * 1997-05-20 2000-03-14 Thomas Jefferson University FADD-like anti-apoptotic molecules, methods of using the same, and compositions for and methods of making the same
EP1012331B1 (en) 1997-07-01 2006-03-29 Isis Pharmaceuticals, Inc. Compositions and methods for the delivery of oligonucleotides via the alimentary canal
WO1999013896A1 (en) 1997-09-18 1999-03-25 The Trustees Of The University Of Pennsylvania Attenuated vif dna immunization cassettes for genetic vaccines
WO1999018946A1 (en) * 1997-10-14 1999-04-22 Tatton Nadine A Methods for increasing schwann cell survival
GB9721901D0 (en) 1997-10-16 1997-12-17 Univ Manchester Particles
US20040258703A1 (en) * 1997-11-14 2004-12-23 The Government Of The Us, As Represented By The Secretary Of The Army Skin-active adjuvants for transcutaneous immunization
WO1999039744A1 (en) * 1998-02-10 1999-08-12 The Ohio State University Research Foundation Compositions and methods for polynucleotide delivery
US20040002079A1 (en) * 1998-02-11 2004-01-01 Gunn Robert B. Sodium-phosphate cotransporter in lithium therapy for the treatment of mental illness
US20020137786A1 (en) * 1998-02-12 2002-09-26 William G. Tatton Deprenyl compounds to treat viral infections and reduce tissue damage associated therewith
US20090011984A1 (en) * 1998-02-23 2009-01-08 Seppo Yla-Herttuala Biotin-binding receptor molecules
US6417168B1 (en) 1998-03-04 2002-07-09 The Trustees Of The University Of Pennsylvania Compositions and methods of treating tumors
US6329356B1 (en) 1998-04-10 2001-12-11 Neurochem, Inc. Phosphono-carboxylate compounds for treating amyloidosis
US6093382A (en) * 1998-05-16 2000-07-25 Bracco Research Usa Inc. Metal complexes derivatized with folate for use in diagnostic and therapeutic applications
EP1080103A4 (en) * 1998-05-21 2003-07-02 Isis Pharmaceuticals Inc Compositions and methods for non-parenteral delivery of oligonucleotides
US6300319B1 (en) 1998-06-16 2001-10-09 Isis Pharmaceuticals, Inc. Targeted oligonucleotide conjugates
US20030219427A1 (en) * 1998-08-18 2003-11-27 Allen Hamish J. TPL-2/COT kinase and methods of use
US6077709A (en) 1998-09-29 2000-06-20 Isis Pharmaceuticals Inc. Antisense modulation of Survivin expression
US6448078B1 (en) 1998-10-09 2002-09-10 The Trustees Of The University Of Pennsylvania Cellular receptor for HIV-1 Vpr essential for G2/M phase transition of the cell cycle
CN100572542C (en) 1998-11-19 2009-12-23 乔治敦大学 Systematicness virus/ligand gene delivery system and gene therapy
US20050063950A1 (en) * 1998-11-19 2005-03-24 Georgetown University Systemic viral/ligand gene delivery system and gene therapy
CA2353593A1 (en) * 1998-12-18 2000-06-22 Hadasit Medical Research Services & Development Ltd. Method of administering a compound to multi-drug resistant cells
US6974698B1 (en) 1999-01-15 2005-12-13 The United States Of America As Represented By The Department Of Health And Human Services Methods for delivering biologically active molecules into cells
JP2003503008A (en) * 1999-03-01 2003-01-28 バリアジェニックス インコーポレーテッド Methods for targeting RNA molecules
US6713280B1 (en) 1999-04-07 2004-03-30 Thomas Jefferson University Enhancement of peptide cellular uptake
US7098192B2 (en) 1999-04-08 2006-08-29 Isis Pharmaceuticals, Inc. Antisense oligonucleotide modulation of STAT3 expression
JP4932086B2 (en) * 1999-04-08 2012-05-16 インターセル ユーエスエイ、インコーポレイテッド Dry formulation for transcutaneous immunization
GB9908195D0 (en) 1999-04-09 1999-06-02 Microbiological Res Authority Treatment of intracellular infection
ATE441421T1 (en) * 1999-04-28 2009-09-15 Bellus Health Int Ltd COMPOSITIONS AND METHODS FOR TREATING AMYLOIDOSIS WITH SULPHONATE DERIVATIVES
US6609113B1 (en) * 1999-05-03 2003-08-19 The Chase Manhattan Bank Method and system for processing internet payments using the electronic funds transfer network
AUPQ014699A0 (en) * 1999-05-04 1999-05-27 Access Pharmaceuticals Australia Pty Limited Amplification of folate-mediated targeting to tumor cells using nanoparticles
US6562836B1 (en) 1999-05-24 2003-05-13 Queen's University Of Kingston Methods and compounds for inhibiting amyloid deposits
US6656730B1 (en) 1999-06-15 2003-12-02 Isis Pharmaceuticals, Inc. Oligonucleotides conjugated to protein-binding drugs
CA2589418A1 (en) 1999-08-24 2001-03-01 Medarex, Inc. Human ctla-4 antibodies and their uses
WO2001013958A2 (en) * 1999-08-26 2001-03-01 Sydney Brenner Drug conjugates and methods of designing the same
US6692724B1 (en) 1999-10-25 2004-02-17 Board Of Regents, The University Of Texas System Ethylenedicysteine (EC)-drug conjugates, compositions and methods for tissue specific disease imaging
US7067111B1 (en) 1999-10-25 2006-06-27 Board Of Regents, University Of Texas System Ethylenedicysteine (EC)-drug conjugates, compositions and methods for tissue specific disease imaging
CA2391534A1 (en) * 1999-11-15 2001-05-25 Drug Innovation & Design, Inc. Selective cellular targeting: multifunctional delivery vehicles
US8571975B1 (en) 1999-11-24 2013-10-29 Jpmorgan Chase Bank, N.A. System and method for sending money via E-mail over the internet
US6933108B2 (en) 1999-12-09 2005-08-23 The Regents Of The University Of California Methods and compositions for use in the treatment of filovirus mediated disease conditions
WO2001041784A1 (en) * 1999-12-09 2001-06-14 The Regents Of The University Of California Methods and compositions for use in the treatment of filovirus mediated disease conditions
US20020055479A1 (en) 2000-01-18 2002-05-09 Cowsert Lex M. Antisense modulation of PTP1B expression
US6261840B1 (en) 2000-01-18 2001-07-17 Isis Pharmaceuticals, Inc. Antisense modulation of PTP1B expression
GB0002814D0 (en) 2000-02-09 2000-03-29 Univ York Nucleic acids and their uses
AU3811101A (en) * 2000-02-11 2001-08-20 Lawrence Blatt Method and reagent for the modulation and diagnosis of cd20 and nogo gene expression
US8202979B2 (en) * 2002-02-20 2012-06-19 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid
US7833992B2 (en) * 2001-05-18 2010-11-16 Merck Sharpe & Dohme Conjugates and compositions for cellular delivery
US7491805B2 (en) * 2001-05-18 2009-02-17 Sirna Therapeutics, Inc. Conjugates and compositions for cellular delivery
US20030176385A1 (en) * 2000-02-15 2003-09-18 Jingfang Ju Antisense modulation of protein expression
AU5697001A (en) * 2000-03-31 2001-10-15 Purdue Research Foundation Method of treatment using ligand-immunogen conjugates
CN1095472C (en) 2000-04-17 2002-12-04 上海复康医药科技发展有限公司 Folica acid-polysaccharide composite and its preparation and medical composition with the composite as active component
US7560534B2 (en) 2000-05-08 2009-07-14 Celldex Research Corporation Molecular conjugates comprising human monoclonal antibodies to dendritic cells
NZ534864A (en) 2000-05-08 2006-04-28 Celldex Therapeutics Inc Human monoclonal antibodies to dentritic cells
US6680172B1 (en) 2000-05-16 2004-01-20 Regents Of The University Of Michigan Treatments and markers for cancers of the central nervous system
BRPI0111220B8 (en) * 2000-06-02 2021-07-27 Univ Texas drug conjugates with ethylenedicysteine (ec)
US20080032942A1 (en) * 2000-08-30 2008-02-07 Mcswiggen James RNA interference mediated treatment of Alzheimer's disease using short interfering nucleic acid (siNA)
US20050209179A1 (en) * 2000-08-30 2005-09-22 Sirna Therapeutics, Inc. RNA interference mediated treatment of Alzheimer's disease using short interfering nucleic acid (siNA)
EP1341497A4 (en) * 2000-11-02 2005-10-19 Smithkline Beecham Corp Receptor antagonist-lipid conjugates and delivery vehicles containing same
WO2002035987A2 (en) * 2000-11-03 2002-05-10 Massachusetts Institute Of Technology METHODS FOR IDENTIFYING TREATMENTS FOR NEUROTOXICITY IN ALZHEIMER'S DISEASE CAUSED BY β-AMYLOID PEPTIDES
US7067550B2 (en) * 2000-11-03 2006-06-27 Massachusetts Institute Of Technology Treatments for neurotoxicity in Alzheimer's Disease
JP2004536027A (en) 2000-12-01 2004-12-02 ジョーンズ・ホプキンス・ユニーバーシティー Glycosylated / galactosylated peptide conjugates, bifunctional linkers, and nucleotide monomers / polymers, and related compositions and methods of use
DE60227157D1 (en) * 2001-02-13 2008-07-31 Us Gov Sec Army IMPREGENTS FOR TRANSCUTANEOUS IMMUNIZATION AGAINST TRAVEL DIARRHOUS
EP1389209B1 (en) * 2001-04-24 2009-04-08 Purdue Research Foundation Folate mimetics and folate-receptor binding conjugates thereof
WO2002087498A2 (en) * 2001-04-26 2002-11-07 Board Of Regents, The University Of Texas System Diagnostic imaging compositions, their methods of synthesis and use
HUP0401127A3 (en) 2001-05-02 2006-03-28 Purdue Research Foundation Treatment and diagnosis of macrophage disease
US20050119212A1 (en) * 2001-05-18 2005-06-02 Sirna Therapeutics, Inc. RNA interference mediated inhibition of FAS and FASL gene expression using short interfering nucleic acid (siNA)
US20050227935A1 (en) * 2001-05-18 2005-10-13 Sirna Therapeutics, Inc. RNA interference mediated inhibition of TNF and TNF receptor gene expression using short interfering nucleic acid (siNA)
US20050136436A1 (en) * 2001-05-18 2005-06-23 Sirna Therapeutics, Inc. RNA interference mediated inhibition of G72 and D-amino acid oxidase (DAAO) gene expression using short interfering nucleic acid (siNA)
US20050222066A1 (en) * 2001-05-18 2005-10-06 Sirna Therapeutics, Inc. RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20050187174A1 (en) * 2001-05-18 2005-08-25 Sirna Therapeutics, Inc. RNA interference mediated inhibition of intercellular adhesion molecule (ICAM) gene expression using short interfering nucleic acid (siNA)
US20050287128A1 (en) * 2001-05-18 2005-12-29 Sirna Therapeutics, Inc. RNA interference mediated inhibition of TGF-beta and TGF-beta receptor gene expression using short interfering nucleic acid (siNA)
US20050176666A1 (en) * 2001-05-18 2005-08-11 Sirna Therapeutics, Inc. RNA interference mediated inhibition of GPRA and AAA1 gene expression using short interfering nucleic acid (siNA)
US20070042983A1 (en) * 2001-05-18 2007-02-22 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA)
US20050119211A1 (en) * 2001-05-18 2005-06-02 Sirna Therapeutics, Inc. RNA mediated inhibition connexin gene expression using short interfering nucleic acid (siNA)
US20040198682A1 (en) * 2001-11-30 2004-10-07 Mcswiggen James RNA interference mediated inhibition of placental growth factor gene expression using short interfering nucleic acid (siNA)
US20050079610A1 (en) * 2001-05-18 2005-04-14 Sirna Therapeutics, Inc. RNA interference mediated inhibition of Fos gene expression using short interfering nucleic acid (siNA)
US20070270579A1 (en) * 2001-05-18 2007-11-22 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA)
US20050203040A1 (en) * 2001-05-18 2005-09-15 Sirna Therapeutics, Inc. RNA interference mediated inhibition of vascular cell adhesion molecule (VCAM) gene expression using short interfering nucleic acid (siNA)
US20050196765A1 (en) * 2001-05-18 2005-09-08 Sirna Therapeutics, Inc. RNA interference mediated inhibition of checkpoint Kinase-1 (CHK-1) gene expression using short interfering nucleic acid (siNA)
US20050191638A1 (en) * 2002-02-20 2005-09-01 Sirna Therapeutics, Inc. RNA interference mediated treatment of polyglutamine (polyQ) repeat expansion diseases using short interfering nucleic acid (siNA)
US20080188430A1 (en) * 2001-05-18 2008-08-07 Sirna Therapeutics, Inc. RNA interference mediated inhibition of hypoxia inducible factor 1 (HIF1) gene expression using short interfering nucleic acid (siNA)
US20050233344A1 (en) * 2001-05-18 2005-10-20 Sirna Therapeutics, Inc. RNA interference mediated inhibition of platelet derived growth factor (PDGF) and platelet derived growth factor receptor (PDGFR) gene expression using short interfering nucleic acid (siNA)
US7517864B2 (en) * 2001-05-18 2009-04-14 Sirna Therapeutics, Inc. RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20050159379A1 (en) * 2001-05-18 2005-07-21 Sirna Therapeutics, Inc RNA interference mediated inhibition of gastric inhibitory polypeptide (GIP) and gastric inhibitory polypeptide receptor (GIPR) gene expression using short interfering nucleic acid (siNA)
US20050182007A1 (en) * 2001-05-18 2005-08-18 Sirna Therapeutics, Inc. RNA interference mediated inhibition of interleukin and interleukin receptor gene expression using short interfering nucleic acid (SINA)
US20050196767A1 (en) * 2001-05-18 2005-09-08 Sirna Therapeutics, Inc. RNA interference mediated inhibition of GRB2 associated binding protein (GAB2) gene expression using short interfering nucleic acis (siNA)
US20050143333A1 (en) * 2001-05-18 2005-06-30 Sirna Therapeutics, Inc. RNA interference mediated inhibition of interleukin and interleukin receptor gene expression using short interfering nucleic acid (SINA)
US20080161256A1 (en) * 2001-05-18 2008-07-03 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA)
JP4358521B2 (en) 2001-05-18 2009-11-04 サーナ・セラピューティクス・インコーポレイテッド Conjugates and compositions for cellular delivery
US20050124566A1 (en) * 2001-05-18 2005-06-09 Sirna Therapeutics, Inc. RNA interference mediated inhibition of myostatin gene expression using short interfering nucleic acid (siNA)
US20050159376A1 (en) * 2002-02-20 2005-07-21 Slrna Therapeutics, Inc. RNA interference mediated inhibition 5-alpha reductase and androgen receptor gene expression using short interfering nucleic acid (siNA)
US9994853B2 (en) 2001-05-18 2018-06-12 Sirna Therapeutics, Inc. Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference
US20050267058A1 (en) * 2001-05-18 2005-12-01 Sirna Therapeutics, Inc. RNA interference mediated inhibition of placental growth factor gene expression using short interfering nucleic acid (sINA)
US20050137155A1 (en) * 2001-05-18 2005-06-23 Sirna Therapeutics, Inc. RNA interference mediated treatment of Parkinson disease using short interfering nucleic acid (siNA)
US20050124567A1 (en) * 2001-05-18 2005-06-09 Sirna Therapeutics, Inc. RNA interference mediated inhibition of TRPM7 gene expression using short interfering nucleic acid (siNA)
US20050233997A1 (en) * 2001-05-18 2005-10-20 Sirna Therapeutics, Inc. RNA interference mediated inhibition of matrix metalloproteinase 13 (MMP13) gene expression using short interfering nucleic acid (siNA)
US20050014172A1 (en) * 2002-02-20 2005-01-20 Ivan Richards RNA interference mediated inhibition of muscarinic cholinergic receptor gene expression using short interfering nucleic acid (siNA)
US20060019913A1 (en) * 2001-05-18 2006-01-26 Sirna Therapeutics, Inc. RNA interference mediated inhibtion of protein tyrosine phosphatase-1B (PTP-1B) gene expression using short interfering nucleic acid (siNA)
US20050130181A1 (en) * 2001-05-18 2005-06-16 Sirna Therapeutics, Inc. RNA interference mediated inhibition of wingless gene expression using short interfering nucleic acid (siNA)
US20050124568A1 (en) * 2001-05-18 2005-06-09 Sirna Therapeutics, Inc. RNA interference mediated inhibition of acetyl-CoA-carboxylase gene expression using short interfering nucleic acid (siNA)
US20050288242A1 (en) * 2001-05-18 2005-12-29 Sirna Therapeutics, Inc. RNA interference mediated inhibition of RAS gene expression using short interfering nucleic acid (siNA)
US20040209831A1 (en) * 2002-02-20 2004-10-21 Mcswiggen James RNA interference mediated inhibition of hepatitis C virus (HCV) gene expression using short interfering nucleic acid (siNA)
US20050282188A1 (en) * 2001-05-18 2005-12-22 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA)
US20060142226A1 (en) * 2001-05-18 2006-06-29 Sirna Therapeutics, Inc. RNA interference mediated inhibition of cholesteryl ester transfer protein (CETP) gene expression using short interfering nucleic acid (siNA)
US20060142225A1 (en) * 2001-05-18 2006-06-29 Sirna Therapeutics, Inc. RNA interference mediated inhibition of cyclin dependent kinase-2 (CDK2) gene expression using short interfering nucleic acid (siNA)
US20060241075A1 (en) * 2001-05-18 2006-10-26 Sirna Therapeutics, Inc. RNA interference mediated inhibition of desmoglein gene expression using short interfering nucleic acid (siNA)
US20050176664A1 (en) * 2001-05-18 2005-08-11 Sirna Therapeutics, Inc. RNA interference mediated inhibition of cholinergic muscarinic receptor (CHRM3) gene expression using short interfering nucleic acid (siNA)
US20050233996A1 (en) * 2002-02-20 2005-10-20 Sirna Therapeutics, Inc. RNA interference mediated inhibition of hairless (HR) gene expression using short interfering nucleic acid (siNA)
US20050182006A1 (en) * 2001-05-18 2005-08-18 Sirna Therapeutics, Inc RNA interference mediated inhibition of protein kinase C alpha (PKC-alpha) gene expression using short interfering nucleic acid (siNA)
US20050164966A1 (en) * 2001-05-18 2005-07-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of type 1 insulin-like growth factor receptor gene expression using short interfering nucleic acid (siNA)
US20050159382A1 (en) * 2001-05-18 2005-07-21 Sirna Therapeutics, Inc. RNA interference mediated inhibition of polycomb group protein EZH2 gene expression using short interfering nucleic acid (siNA)
US20050159380A1 (en) * 2001-05-18 2005-07-21 Sirna Therapeutics, Inc. RNA interference mediated inhibition of angiopoietin gene expression using short interfering nucleic acid (siNA)
US20050153914A1 (en) * 2001-05-18 2005-07-14 Sirna Therapeutics, Inc. RNA interference mediated inhibition of MDR P-glycoprotein gene expression using short interfering nucleic acid (siNA)
US20050153915A1 (en) * 2001-05-18 2005-07-14 Sirna Therapeutics, Inc. RNA interference mediated inhibition of early growth response gene expression using short interfering nucleic acid (siNA)
US20030130186A1 (en) * 2001-07-20 2003-07-10 Chandra Vargeese Conjugates and compositions for cellular delivery
US20050164968A1 (en) * 2001-05-18 2005-07-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of ADAM33 gene expression using short interfering nucleic acid (siNA)
US7109165B2 (en) * 2001-05-18 2006-09-19 Sirna Therapeutics, Inc. Conjugates and compositions for cellular delivery
US20050054598A1 (en) * 2002-02-20 2005-03-10 Sirna Therapeutics, Inc. RNA interference mediated inhibition hairless (HR) gene expression using short interfering nucleic acid (siNA)
US20050164224A1 (en) * 2001-05-18 2005-07-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of cyclin D1 gene expression using short interfering nucleic acid (siNA)
US20050080031A1 (en) * 2001-05-18 2005-04-14 Sirna Therapeutics, Inc. Nucleic acid treatment of diseases or conditions related to levels of Ras, HER2 and HIV
US20050164967A1 (en) * 2001-05-18 2005-07-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of platelet-derived endothelial cell growth factor (ECGF1) gene expression using short interfering nucleic acid (siNA)
US20050209180A1 (en) * 2001-05-18 2005-09-22 Sirna Therapeutics, Inc. RNA interference mediated inhibition of hepatitis C virus (HCV) expression using short interfering nucleic acid (siNA)
US20060211642A1 (en) * 2001-05-18 2006-09-21 Sirna Therapeutics, Inc. RNA inteference mediated inhibition of hepatitis C virus (HVC) gene expression using short interfering nucleic acid (siNA)
US20050182009A1 (en) * 2001-05-18 2005-08-18 Sirna Therapeutics, Inc. RNA interference mediated inhibition of NF-Kappa B / REL-A gene expression using short interfering nucleic acid (siNA)
US20050176665A1 (en) * 2001-05-18 2005-08-11 Sirna Therapeutics, Inc. RNA interference mediated inhibition of hairless (HR) gene expression using short interfering nucleic acid (siNA)
US20050256068A1 (en) * 2001-05-18 2005-11-17 Sirna Therapeutics, Inc. RNA interference mediated inhibition of stearoyl-CoA desaturase (SCD) gene expression using short interfering nucleic acid (siNA)
CA2633171C (en) 2001-06-20 2012-11-20 Genentech, Inc. Antibodies against tumor-associated antigenic target (tat) polypeptides
US7803915B2 (en) * 2001-06-20 2010-09-28 Genentech, Inc. Antibody compositions for the diagnosis and treatment of tumor
US20050107595A1 (en) * 2001-06-20 2005-05-19 Genentech, Inc. Compositions and methods for the diagnosis and treatment of tumor
AU2002315393A1 (en) 2001-06-21 2003-01-08 Isis Pharmaceuticals, Inc. Antisense modulation of superoxide dismutase 1, soluble expression
US20030031677A1 (en) * 2001-06-25 2003-02-13 Drug Innovation & Design, Incorporated Exponential pattern recognition based cellular targeting, compositions, methods and anticancer applications
US6964950B2 (en) 2001-07-25 2005-11-15 Isis Pharmaceuticals, Inc. Antisense modulation of C-reactive protein expression
US7425545B2 (en) 2001-07-25 2008-09-16 Isis Pharmaceuticals, Inc. Modulation of C-reactive protein expression
US20030096772A1 (en) 2001-07-30 2003-05-22 Crooke Rosanne M. Antisense modulation of acyl CoA cholesterol acyltransferase-2 expression
US7407943B2 (en) 2001-08-01 2008-08-05 Isis Pharmaceuticals, Inc. Antisense modulation of apolipoprotein B expression
US7227014B2 (en) 2001-08-07 2007-06-05 Isis Pharmaceuticals, Inc. Antisense modulation of apolipoprotein (a) expression
DE60238143D1 (en) 2001-09-18 2010-12-09 Genentech Inc COMPOSITIONS AND METHODS FOR THE DIAGNOSIS OF TUMORS
DE60234782D1 (en) * 2001-09-28 2010-01-28 Purdue Research Foundation TREATMENT PROCEDURE WITH LIGAND IMMUNOGENIC CONJUGATES
US6750019B2 (en) 2001-10-09 2004-06-15 Isis Pharmaceuticals, Inc. Antisense modulation of insulin-like growth factor binding protein 5 expression
NZ577565A (en) 2001-10-09 2010-10-29 Isis Pharmaceuticals Inc Antisense modulation of insulin-like growth factor binding protein 5 expressions
WO2004033620A2 (en) 2001-11-02 2004-04-22 Insert Therapeutics, Inc. Methods and compositions for therapeutic use of rna interference
US6965025B2 (en) 2001-12-10 2005-11-15 Isis Pharmaceuticals, Inc. Antisense modulation of connective tissue growth factor expression
US7261875B2 (en) * 2001-12-21 2007-08-28 Board Of Regents, The University Of Texas System Dendritic poly (amino acid) carriers and methods of use
US7255874B1 (en) 2001-12-21 2007-08-14 Closure Medical Corporation Biocompatible polymers and adhesives: compositions, methods of making and uses related thereto
WO2003057160A2 (en) 2002-01-02 2003-07-17 Genentech, Inc. Compositions and methods for the diagnosis and treatment of tumor
US8043602B2 (en) 2002-02-07 2011-10-25 Endocyte, Inc. Folate targeted enhanced tumor and folate receptor positive tissue optical imaging technology
US8043603B2 (en) 2002-02-07 2011-10-25 Endocyte, Inc. Folate targeted enhanced tumor and folate receptor positive tissue optical imaging technology
US20050137153A1 (en) * 2002-02-20 2005-06-23 Sirna Therapeutics, Inc. RNA interference mediated inhibition of alpha-1 antitrypsin (AAT) gene expression using short interfering nucleic acid (siNA)
US9657294B2 (en) 2002-02-20 2017-05-23 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20050222064A1 (en) * 2002-02-20 2005-10-06 Sirna Therapeutics, Inc. Polycationic compositions for cellular delivery of polynucleotides
US20050096284A1 (en) * 2002-02-20 2005-05-05 Sirna Therapeutics, Inc. RNA interference mediated treatment of polyglutamine (polyQ) repeat expansion diseases using short interfering nucleic acid (siNA)
US9181551B2 (en) 2002-02-20 2015-11-10 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20030191075A1 (en) * 2002-02-22 2003-10-09 Cook Phillip Dan Method of using modified oligonucleotides for hepatic delivery
US20030180712A1 (en) 2002-03-20 2003-09-25 Biostratum Ab Inhibition of the beta3 subunit of L-type Ca2+ channels
US7737264B2 (en) 2002-04-05 2010-06-15 Enzon Pharmaceuticals, Inc. Oligomeric compounds for the modulation HIF-1α expression
MXPA04010092A (en) 2002-04-16 2004-12-13 Genentech Inc Compositions and methods for the diagnosis and treatment of tumor.
AU2003224989B2 (en) * 2002-04-19 2008-12-04 Endocyte, Inc. Adjuvant enhanced immunotherapy
US20030206916A1 (en) * 2002-05-03 2003-11-06 Rush-Presbyterian-St. Luke's Medical Center Immunogenic peptides
EP1549352A4 (en) 2002-05-06 2005-07-27 Nucleonics Inc Methods for delivery of nucleic acids
US7910594B2 (en) * 2002-05-15 2011-03-22 Endocyte, Inc. Vitamin-mitomycin conjugates
US7199107B2 (en) 2002-05-23 2007-04-03 Isis Pharmaceuticals, Inc. Antisense modulation of kinesin-like 1 expression
ATE522130T1 (en) 2002-07-19 2011-09-15 Univ South Carolina COMPOSITIONS AND METHODS FOR MODULATING GENE EXPRESSION IN PLANTS
ATE405658T1 (en) 2002-07-26 2008-09-15 Basf Plant Science Gmbh NEW SELECTION PROCEDURES
EP2277551B1 (en) 2002-09-06 2013-05-08 Cerulean Pharma Inc. Cyclodextrin-based polymers for delivering the therapeutic agents covalently bound thereto
CN1694959B (en) 2002-09-13 2013-09-18 雷普利瑟公司 Non-sequence complementary antiviral oligonucleotides
EP1549767A4 (en) 2002-09-26 2006-06-07 Amgen Inc Modulation of forkhead box o1a expression
CA3029035C (en) 2002-10-17 2023-03-07 Genmab A/S Human monoclonal antibodies against cd20
WO2004110345A2 (en) * 2002-10-29 2004-12-23 Pharmacia Corporation Differentially expressed genes involved in cancer, the polypeptides encoded thereby, and methods of using the same
CA2504929C (en) 2002-11-05 2014-07-22 Charles Allerson Compositions comprising alternating 2'-modified nucleosides for use in gene modulation
CA2504720C (en) 2002-11-05 2013-12-24 Isis Pharmaceuticals, Inc. Chimeric oligomeric compounds and their use in gene modulation
US20040166058A1 (en) * 2002-11-07 2004-08-26 Board Of Regents, The University Of Texas System Ethylenedicysteine (EC)-drug conjugates, compositions and methods for tissue specific disease imaging
AU2003290718A1 (en) * 2002-11-12 2004-07-22 The Research Foundation Of The State University Of New York TRANSLATIONAL CONTROL BY SMALL, NON-TRANSLATABLE RNAs
EP2336318B1 (en) 2002-11-13 2013-04-24 Genzyme Corporation Antisense modulation of apolipoprotein b expression
ES2420914T3 (en) 2002-11-13 2013-08-27 Genzyme Corporation Antisense modulation of apolipoprotein B expression
AU2002953073A0 (en) * 2002-11-21 2003-01-16 Access Pharmaceuticals Australia Pty Limited Amplification of biotin-mediated targeting
DE10254601A1 (en) 2002-11-22 2004-06-03 Ganymed Pharmaceuticals Ag Gene products differentially expressed in tumors and their use
US7144999B2 (en) 2002-11-23 2006-12-05 Isis Pharmaceuticals, Inc. Modulation of hypoxia-inducible factor 1 alpha expression
US20040231231A1 (en) * 2002-12-20 2004-11-25 Cataldo Dominic A. Use of colloidal clays for sustained release of active ingredients
EP2517730A3 (en) 2003-01-27 2013-01-02 Endocyte, Inc. Vitamin receptor binding drug delivery conjugates
US7713738B2 (en) * 2003-02-10 2010-05-11 Enzon Pharmaceuticals, Inc. Oligomeric compounds for the modulation of survivin expression
ES2400033T3 (en) 2003-02-11 2013-04-05 Antisense Therapeutics Ltd Modulation of insulin-like growth factor I receptor expression
US7803781B2 (en) 2003-02-28 2010-09-28 Isis Pharmaceuticals, Inc. Modulation of growth hormone receptor expression and insulin-like growth factor expression
US20040185559A1 (en) 2003-03-21 2004-09-23 Isis Pharmaceuticals Inc. Modulation of diacylglycerol acyltransferase 1 expression
US7598227B2 (en) 2003-04-16 2009-10-06 Isis Pharmaceuticals Inc. Modulation of apolipoprotein C-III expression
WO2004093788A2 (en) * 2003-04-17 2004-11-04 The Trustees Of Columbia University In The City Ofnew York Desmoglein 4 is a novel gene involved in hair growth
CA2523142A1 (en) 2003-04-23 2004-11-04 Medarex, Inc. Humanized antibodies to interferon alpha receptor-1 (ifnar-1)
US7399853B2 (en) 2003-04-28 2008-07-15 Isis Pharmaceuticals Modulation of glucagon receptor expression
EP3222294A1 (en) 2003-04-30 2017-09-27 Sirna Therapeutics, Inc. Conjugates and compositions for cellular delivery
CA2524441C (en) * 2003-05-06 2012-03-20 Purdue Research Foundation Treatment of lupus targeting the macrophages or the folate receptor
WO2004110250A2 (en) 2003-05-30 2004-12-23 Purdue Research Foundation Diagnostic method for atherosclerosis
IL156263A0 (en) * 2003-06-02 2004-01-04 Hadasit Med Res Service Livin-derived peptides, compositions and uses thereof
BRPI0410886A (en) 2003-06-03 2006-07-04 Isis Pharmaceuticals Inc double stranded compound, pharmaceutical composition, pharmaceutically acceptable salt, methods of modifying human survivin-encoding nucleic acid, inhibiting suvivin expression in cells or tissues, and treating a condition associated with suvivin expression or overexpression, and single stranded RNA oligonucleotide
AU2004245074A1 (en) * 2003-06-04 2004-12-16 Canji, Inc Methods and compositions for interferon therapy
WO2005002508A2 (en) * 2003-06-11 2005-01-13 Access Pharmaceuticals, Inc. Macromolecular platinum chelates
US20050142191A1 (en) 2003-06-23 2005-06-30 Neurochem (International) Limited Pharmaceutical formulations of amyloid inhibiting compounds
US20070010573A1 (en) * 2003-06-23 2007-01-11 Xianqi Kong Methods and compositions for treating amyloid-related diseases
US7244764B2 (en) * 2003-06-23 2007-07-17 Neurochem (International) Limited Methods and compositions for treating amyloid-related diseases
US7414076B2 (en) * 2003-06-23 2008-08-19 Neurochem (International) Limited Methods and compositions for treating amyloid-related diseases
US7812116B2 (en) * 2003-07-03 2010-10-12 Rush University Medical Center Immunogenic peptides
EP1502954A1 (en) 2003-07-31 2005-02-02 greenovation Biotech GmbH Utilisation of constructs comprising recombination sequence motifes for enhancing gene expression in moss
CA2533701A1 (en) 2003-07-31 2005-02-17 Isis Pharmaceuticals, Inc. Oligomeric compounds and compositions for use in modulation of small non-coding rnas
US7825235B2 (en) 2003-08-18 2010-11-02 Isis Pharmaceuticals, Inc. Modulation of diacylglycerol acyltransferase 2 expression
US20070123480A1 (en) * 2003-09-11 2007-05-31 Replicor Inc. Oligonucleotides targeting prion diseases
US7425544B2 (en) 2003-09-18 2008-09-16 Eli Lilly And Company Modulation of eIF4E expression
NZ546272A (en) 2003-10-10 2009-05-31 Alchemia Oncology Pty Ltd The modulation of hyaluronan synthesis and degradation in the treatment of disease
US20050191653A1 (en) 2003-11-03 2005-09-01 Freier Susan M. Modulation of SGLT2 expression
WO2005046730A2 (en) * 2003-11-12 2005-05-26 The University Of Georgia Research Foundation, Inc. Biotin-facilitated transport into gram negative bacteria
EP1689432B1 (en) 2003-11-17 2009-12-30 Genentech, Inc. Compositions and methods for the treatment of tumor of hematopoietic origin
US20050118124A1 (en) * 2003-12-01 2005-06-02 Reinhart Gale M. Compositions for treating keratinous surfaces
JP4942487B2 (en) 2003-12-10 2012-05-30 メダレックス インコーポレーティッド IP-10 antibody and use thereof
EP2418220B1 (en) 2003-12-10 2017-08-02 E. R. Squibb & Sons, L.L.C. Interferon alpha antibodies and their uses
US9050378B2 (en) * 2003-12-10 2015-06-09 Board Of Regents, The University Of Texas System N2S2 chelate-targeting ligand conjugates
FR2864085B1 (en) * 2003-12-18 2010-09-17 Centre Nat Rech Scient NEW MODULATORS OF PROTEASOME
CN100569945C (en) 2003-12-23 2009-12-16 桑塔里斯制药公司 Be used to regulate the oligomeric compounds of BCL-2
WO2005071080A2 (en) 2004-01-20 2005-08-04 Isis Pharmaceuticals, Inc. Modulation of glucocorticoid receptor expression
US7468431B2 (en) 2004-01-22 2008-12-23 Isis Pharmaceuticals, Inc. Modulation of eIF4E-BP2 expression
EP1732608A2 (en) * 2004-01-22 2006-12-20 Immunomedics, Inc. Folate conjugates and complexes
EP1713900A4 (en) * 2004-01-27 2009-06-17 Compugen Ltd Methods and systems for annotating biomolecular sequences
EP1716179A2 (en) 2004-02-12 2006-11-02 Morphotek, Inc. Monoclonal antibodies that specifically bind to folate receptor alpha
US8569474B2 (en) 2004-03-09 2013-10-29 Isis Pharmaceuticals, Inc. Double stranded constructs comprising one or more short strands hybridized to a longer strand
US8790919B2 (en) 2004-03-15 2014-07-29 Isis Pharmaceuticals, Inc. Compositions and methods for optimizing cleavage of RNA by RNase H
US10858384B2 (en) 2004-03-22 2020-12-08 Kode Biotech Limited Synthetic molecule constructs
US8013131B2 (en) 2004-03-22 2011-09-06 Kode Biotech Limited Synthetic membrane anchors
DK1730280T3 (en) * 2004-03-26 2019-02-04 Curis Inc RNA interference modulators for hedgehog signaling and applications thereof
US20080253960A1 (en) * 2004-04-01 2008-10-16 The Trustees Of The University Of Pennsylvania Center For Technology Transfer Lipoprotein-Based Nanoplatforms
US20050244869A1 (en) * 2004-04-05 2005-11-03 Brown-Driver Vickie L Modulation of transthyretin expression
AU2005323437B2 (en) * 2004-04-30 2011-10-06 Alnylam Pharmaceuticals, Inc. Oligonucleotides comprising a C5-modified pyrimidine
DE102004024617A1 (en) 2004-05-18 2005-12-29 Ganymed Pharmaceuticals Ag Differentially expressed in tumors gene products and their use
US10508277B2 (en) 2004-05-24 2019-12-17 Sirna Therapeutics, Inc. Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference
US20060229267A1 (en) 2004-06-01 2006-10-12 Reza Sheikhnejad Methods and compositions for the inhibition of gene expression
US20050272100A1 (en) * 2004-06-02 2005-12-08 Arthur Karlin Separation and quantification of biotinylated macromolecules
CA2569419A1 (en) * 2004-06-03 2005-12-22 Isis Pharmaceuticals, Inc. Double strand compositions comprising differentially modified strands for use in gene modulation
US20090048192A1 (en) * 2004-06-03 2009-02-19 Isis Pharmaceuticals, Inc. Double Strand Compositions Comprising Differentially Modified Strands for Use in Gene Modulation
US8394947B2 (en) 2004-06-03 2013-03-12 Isis Pharmaceuticals, Inc. Positionally modified siRNA constructs
CA2569036A1 (en) * 2004-06-03 2005-12-22 Balkrishen Bhat Chimeric gapped oligomeric compositions
WO2006002177A2 (en) 2004-06-21 2006-01-05 Medarex, Inc. Interferon alpha receptor 1 antibodies and their uses
WO2006002262A2 (en) 2004-06-21 2006-01-05 The Board Of Trustees Of The Leland Stanford Junior University Genes and pathways differentially expressed in bipolar disorder and/or major depressive disorder
CN101098854B (en) 2004-07-23 2012-12-05 恩多塞特公司 Bivalent linkers and conjugates thereof
US7884086B2 (en) 2004-09-08 2011-02-08 Isis Pharmaceuticals, Inc. Conjugates for use in hepatocyte free uptake assays
US9315862B2 (en) * 2004-10-05 2016-04-19 California Institute Of Technology Aptamer regulated nucleic acids and uses thereof
US9447138B2 (en) 2004-11-09 2016-09-20 Roche Innovation Center Copenhagen A/S Potent LNA oligonucleotides for the inhibition of HIF-1a expression
US20060154888A1 (en) * 2004-11-09 2006-07-13 Santaris Pharma A/S LNA oligonucleotides and the treatment of cancer
DE602005022768D1 (en) * 2004-11-09 2010-09-16 Santaris Pharma As EFFECTIVE LNA OLIGONUCLEOTIDES FOR INHIBITING HIF-1A
BRPI0517790A (en) * 2004-11-12 2008-10-21 Neurochem Int Ltd fluorinated methods and compositions for treating amyloid-related diseases
CA2629751A1 (en) 2004-11-12 2006-05-18 The University Of British Columbia Antimicrobial peptides
CN101103018A (en) * 2004-11-16 2008-01-09 神经化学（国际）有限公司 Compounds for the treatment of CNS and amyloid associated diseases
CA2592320C (en) * 2004-12-22 2015-11-24 Neurochem (International) Limited Methods and compositions for treating amyloid-related diseases
EP2452695A3 (en) * 2004-12-23 2013-01-23 Purdue Research Foundation Positron emission tomography imaging method
WO2006086667A2 (en) 2005-02-09 2006-08-17 Avi Bio Pharma, Inc. Antisense composition and method for treating muscle atrophy
CN101175769A (en) 2005-03-10 2008-05-07 健泰科生物技术公司 Methods and compositions for modulating vascular integrity
CN101175757B (en) * 2005-03-16 2012-11-14 恩多塞特公司 Synthesis and purification of pteroic acid and conjugates thereof
US7829673B2 (en) 2005-03-23 2010-11-09 Genmab A/S Antibodies against CD38 for treatment of multiple myeloma
EP1866414B9 (en) 2005-03-31 2012-10-03 Calando Pharmaceuticals, Inc. Inhibitors of ribonucleotide reductase subunit 2 and uses thereof
AU2006241099B2 (en) 2005-04-22 2012-04-19 Eisai, Inc. Antibodies with immune effector activity and that internalize in folate receptor alpha-positive cells
EP1896582A4 (en) 2005-05-09 2009-04-08 Ono Pharmaceutical Co Human monoclonal antibodies to programmed death 1(pd-1) and methods for treating cancer using anti-pd-1 antibodies alone or in combination with other immunotherapeutics
EA200800094A1 (en) 2005-06-20 2008-06-30 Медарекс, Инк. ANTIBODIES CD19 AND THEIR USE
CN101248089A (en) 2005-07-01 2008-08-20 米德列斯公司 Human monoclonal antibodies to programmed death ligand 1(PD-L1)
JP5175723B2 (en) * 2005-07-05 2013-04-03 パーデュー・リサーチ・ファウンデーション Preparation of compositions for treating monocyte-mediated diseases
US20090176725A1 (en) * 2005-08-17 2009-07-09 Sirna Therapeutics Inc. Chemically modified short interfering nucleic acid molecules that mediate rna interference
EP1948240A2 (en) * 2005-08-19 2008-07-30 Endocyte, Inc. Ligand conjugates of vinca alkaloids, analogs and derivatives
CN103893779A (en) * 2005-08-19 2014-07-02 恩多塞特公司 Multi-drug ligand conjugates
EP1957093B1 (en) 2005-08-29 2017-04-12 SHASHOUA, Victor E. Neuroprotective and neurorestorative methods and compositions
EP1762575A1 (en) 2005-09-12 2007-03-14 Ganymed Pharmaceuticals AG Identification of tumor-associated antigens for diagnosis and therapy
EP1931778A2 (en) * 2005-09-15 2008-06-18 Santaris Pharma A/S RNA ANTAGONIST COMPOUNDS FOR THE INHIBITION OF APO-Bl00 EXPRESSION
US8795633B2 (en) * 2005-09-23 2014-08-05 Purdue Research Foundation Multiphoton in vivo flow cytometry method and device
AU2006294663B2 (en) 2005-09-26 2012-03-22 Medarex, Inc. Human monoclonal antibodies to CD70
AR058104A1 (en) 2005-10-21 2008-01-23 Novartis Ag ORGANIC COMPOUNDS
US20070099246A1 (en) * 2005-11-03 2007-05-03 Sandy John D Antibodies, assays and kits to quantitate cartilage destruction
JP5366554B2 (en) 2005-11-12 2013-12-11 ザ ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティー FGF2-related methods for diagnosing and treating depression
JP2009516710A (en) 2005-11-21 2009-04-23 アイシス ファーマシューティカルズ， インコーポレーテッド Modulating the expression of eIF4E-BP2
EP1790664A1 (en) 2005-11-24 2007-05-30 Ganymed Pharmaceuticals AG Monoclonal antibodies against claudin-18 for treatment of cancer
WO2007064945A2 (en) 2005-12-01 2007-06-07 Pronai Therapeutics, Inc. Cancer therapies and pharmaceutical compositions used therein
CN101356195B (en) 2005-12-08 2013-04-03 米德列斯公司 Human monoclonal antibodies to fucosyl-GM1 and methods for using anti-fucosyl-GM1
IL173104A0 (en) 2006-01-12 2006-06-11 Yeda Res & Dev Siva and ubiquintination
US20090175886A1 (en) 2006-01-17 2009-07-09 Medarex, Inc. Monoclonal antibodies against cd30 lacking in fucosyl and xylosyl residues
EP2422819B1 (en) 2006-01-26 2017-03-01 Ionis Pharmaceuticals, Inc. Compositions and their uses directed to Huntingtin
US8168164B2 (en) * 2006-02-03 2012-05-01 Purdue Research Foundation Targeted conjugates and radiation
GB0603683D0 (en) 2006-02-23 2006-04-05 Novartis Ag Organic compounds
US20070232556A1 (en) * 2006-03-31 2007-10-04 Montine Thomas J Methods and compositions for the treatment of neurological diseases and disorders
WO2007126455A2 (en) 2006-04-05 2007-11-08 Genentech, Inc. Method for using boc/cdo to modulate hedgehog signaling
US8758723B2 (en) 2006-04-19 2014-06-24 The Board Of Regents Of The University Of Texas System Compositions and methods for cellular imaging and therapy
WO2007124082A2 (en) * 2006-04-21 2007-11-01 Amgen, Inc. Buffering agents for biopharmaceutical formulations
EP2027154B1 (en) 2006-04-21 2012-04-18 Amgen Inc. Immunoglobulin constant region domains with enhanced stability
US20070258941A1 (en) * 2006-05-02 2007-11-08 Pfister Brian E Methods and compositions for remediation of disc herniation by modifying structure
WO2007131034A1 (en) * 2006-05-03 2007-11-15 The Regents Of The University Of Michigan Pyrimidone derivatives which are modulators of heat shock protein (hsp) 70
MX2008014005A (en) * 2006-05-03 2009-01-27 Baltic Technology Dev Ltd Antisense agents combining strongly bound base - modified oligonucleotide and artificial nuclease.
US20090209625A1 (en) * 2006-05-23 2009-08-20 Sanjay Bhanot Modulation of chrebp expression
US20100226967A1 (en) * 2006-05-23 2010-09-09 Purdue Research Foundation Imaging and therapeutic method using progenitor cells
AR061181A1 (en) * 2006-05-25 2008-08-13 Bristol Myers Squibb Co AZIRIDINIL-EPOTILONE COMPOUNDS
PE20080102A1 (en) * 2006-05-25 2008-02-11 Bristol Myers Squibb Co AZIRIDINYL-EPOTILONE CONJUGATES AND PHARMACEUTICAL COMPOSITIONS INCLUDING THE SAME
ES2286951B1 (en) * 2006-05-26 2008-10-01 Instituto Cientifico Y Tecnologico De Navarra, S.A BIOADHESIVE NANOPARTICLES FOR THE ADMINISTRATION OF BIOLOGICALLY ACTIVE MOLECULES.
DK2193801T3 (en) 2006-06-28 2012-03-26 Yeda Res & Dev Caspase-8 and wound healing
US8198253B2 (en) 2006-07-19 2012-06-12 Isis Pharmaceuticals, Inc. Compositions and their uses directed to HBXIP
US20100316626A1 (en) * 2006-08-11 2010-12-16 The Government Of The United States Of America As Represented By The Secretary Methods for treatment and diagnosis of psychiatric disorders
KR20090088852A (en) 2006-09-05 2009-08-20 메다렉스, 인코포레이티드 Antibodies to bone morphogenic proteins and receptors therefor and methods for their use
PL2066351T3 (en) 2006-10-02 2016-02-29 Squibb & Sons Llc Human antibodies that bind cxcr4 and uses thereof
US10925977B2 (en) 2006-10-05 2021-02-23 Ceil>Point, LLC Efficient synthesis of chelators for nuclear imaging and radiotherapy: compositions and applications
WO2008045373A2 (en) * 2006-10-06 2008-04-17 Amgen Inc. Stable antibody formulations
EP2862581B1 (en) 2006-10-12 2021-08-11 BHI Limited Partnership Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
ES2925992T3 (en) * 2006-10-20 2022-10-20 Amgen Inc Stable formulations of polypeptides
US8618248B2 (en) 2006-10-31 2013-12-31 President And Fellows Of Harvard College Phosphopeptide compositions and anti-phosphopeptide antibody compositions and methods of detecting phosphorylated peptides
EP2087337A4 (en) 2006-11-03 2010-09-08 Purdue Research Foundation Ex vivo flow cytometry method and device
US8158595B2 (en) 2006-11-09 2012-04-17 California Institute Of Technology Modular aptamer-regulated ribozymes
CL2007003291A1 (en) 2006-11-15 2008-07-04 Medarex Inc ISOLATED HUMAN MONOCLONAL ANTIBODY THAT LINKS THE BTLA PROTEIN OR FRAGMENTS OF THE SAME; NUCLEIC ACID THAT CODIFIES IT; METHOD OF PRODUCTION; COMPOSITION AND IMMUNOCUJUGADO THAT UNDERSTANDS THEM; AND METHOD TO INHIBIT THE GROWTH OF TUMOR CELLS AND
NZ578064A (en) 2006-12-01 2012-01-12 Medarex Inc Human antibodies that bind cd22 and uses thereof
CL2007003622A1 (en) 2006-12-13 2009-08-07 Medarex Inc Human anti-cd19 monoclonal antibody; composition comprising it; and tumor cell growth inhibition method.
KR20090088946A (en) 2006-12-14 2009-08-20 메다렉스, 인코포레이티드 Human antibodies that bind cd70 and uses thereof
EP2118118B1 (en) * 2007-01-19 2017-09-27 Exiqon A/S Mediated cellular delivery of lna oligonucleotides
JP2010516625A (en) 2007-01-24 2010-05-20 インサート セラピューティクス， インコーポレイテッド Polymer-drug conjugates with tether groups for controlled drug delivery
US20100093836A1 (en) 2007-01-29 2010-04-15 Isis Pharmaceuticals, Inc Compounds and methods for modulating protein expression
WO2008098112A2 (en) * 2007-02-07 2008-08-14 Purdue Research Foundation Positron emission tomography imaging method
WO2008101231A2 (en) * 2007-02-16 2008-08-21 Endocyte, Inc. Methods and compositions for treating and diagnosing kidney disease
KR101598229B1 (en) 2007-02-16 2016-02-26 메리맥 파마슈티컬즈, 인크. 3 antibodies against erbb3 and uses thereof
ES2556380T3 (en) 2007-02-22 2016-01-15 Genentech, Inc. Procedures to detect inflammatory bowel disease
AU2008224988A1 (en) * 2007-03-14 2008-09-18 Endocyte, Inc. Binding ligand linked drug delivery conjugates of tubulysins
EP1970384A1 (en) 2007-03-14 2008-09-17 Ganymed Pharmaceuticals AG Monoclonal antibodies for treatment of cancer
US8153863B2 (en) 2007-03-23 2012-04-10 New York University Transgenic plants expressing GLK1 and CCA1 having increased nitrogen assimilation capacity
WO2008118970A2 (en) 2007-03-27 2008-10-02 Sea Lane Biotechnologies, Llc Constructs and libraries comprising antibody surrogate light chain sequences
CA2685269C (en) * 2007-04-27 2014-07-08 Kode Biotech Limited Carbohydrate-lipid constructs and their use in preventing or treating viral infection
GB0709835D0 (en) 2007-05-22 2007-07-04 Plant Bioscience Ltd Composition and method for modulating plant root hair development
EP2164989B1 (en) 2007-05-23 2018-01-24 The Trustees Of The University Of Pennsylvania Targeted carriers for intracellular drug delivery
CA2688308A1 (en) * 2007-05-25 2008-12-04 Purdue Research Foundation Method of imaging localized infections
EP2152717A1 (en) 2007-05-25 2010-02-17 Bristol-Myers Squibb Company Processes for making epothilone compounds and analogs
EP1997832A1 (en) 2007-05-29 2008-12-03 Ganymed Pharmaceuticals AG Monoclonal antibodies against Claudin-18 for treatment of cancer
AU2008268432B2 (en) * 2007-06-25 2015-01-15 Endocyte, Inc. Conjugates containing hydrophilic spacer linkers
US9877965B2 (en) 2007-06-25 2018-01-30 Endocyte, Inc. Vitamin receptor drug delivery conjugates for treating inflammation
WO2009011855A2 (en) * 2007-07-16 2009-01-22 California Institute Of Technology Selection of nucleic acid-based sensor domains within nucleic acid switch platform
US20090155275A1 (en) 2007-07-31 2009-06-18 Medimmune, Llc Multispecific epitope binding proteins and uses thereof
JP5588866B2 (en) 2007-08-10 2014-09-10 メダレックス エル．エル．シー． HCO 32 and HCO 27 and related examples
US20120165387A1 (en) 2007-08-28 2012-06-28 Smolke Christina D General composition framework for ligand-controlled RNA regulatory systems
US8367815B2 (en) * 2007-08-28 2013-02-05 California Institute Of Technology Modular polynucleotides for ligand-controlled regulatory systems
US8394391B2 (en) * 2007-08-31 2013-03-12 University Of Utah Research Foundation Drug delivery vehicle that mimics viral properties
PL2769729T3 (en) 2007-09-04 2019-09-30 Compugen Ltd. Polypeptides and polynucleotides, and uses thereof as a drug target for producing drugs and biologics
US8865667B2 (en) * 2007-09-12 2014-10-21 California Institute Of Technology Higher-order cellular information processing devices
EP2205741A2 (en) 2007-10-02 2010-07-14 Amgen Inc. Increasing erythropoietin using nucleic acids hybridizable to micro-rna and precursors thereof
AR068767A1 (en) 2007-10-12 2009-12-02 Novartis Ag ANTIBODIES AGAINST SCLEROSTIN, COMPOSITIONS AND METHODS OF USE OF THESE ANTIBODIES TO TREAT A PATHOLOGICAL DISORDER MEDIATIONED BY SCLEROSTIN
WO2009055562A1 (en) 2007-10-25 2009-04-30 Endocyte, Inc. Tubulysins and processes for preparing
AU2008320823B2 (en) 2007-11-02 2013-01-17 Novartis Ag Molecules and methods for modulating low-density-lipoprotein receptor-related protein 6 (LRP6)
JP2011502502A (en) * 2007-11-05 2011-01-27 バルティック テクロノジー デヴェロプメント，リミテッド Use of oligonucleotides containing modified bases in nucleic acid hybridization
US8236318B2 (en) 2007-11-07 2012-08-07 Celldex Therapeutics Inc. Antibodies that bind human dendritic and epithelial cell 205 (DEC-205)
CA2705808A1 (en) * 2007-11-15 2009-05-22 Endocyte, Inc. Method of administering conjugates
CN101925364B (en) 2007-11-27 2014-04-30 不列颠哥伦比亚大学 14-3-3 antagonists for prevention and treatment of arthritis
US8507455B2 (en) 2007-12-04 2013-08-13 Alnylam Pharmaceuticals, Inc. Folate conjugates
AU2008340355B2 (en) 2007-12-04 2015-01-22 Tekmira Pharmaceuticals Corporation Targeting lipids
US9029524B2 (en) * 2007-12-10 2015-05-12 California Institute Of Technology Signal activated RNA interference
ES2613963T3 (en) 2008-01-18 2017-05-29 Medimmune, Llc Cysteine manipulated antibodies for site specific conjugation
WO2009100110A1 (en) 2008-02-05 2009-08-13 Medarex, Inc. Alpha 5 - beta 1 antibodies and their uses
PT2250279E (en) 2008-02-08 2016-06-03 Medimmune Llc Anti-ifnar1 antibodies with reduced fc ligand affinity
US8470772B2 (en) 2008-02-27 2013-06-25 Temple University—Of the Commonwealth System of Higher Education Leptin agonist and methods of use
CN102014937A (en) 2008-03-03 2011-04-13 迈阿密大学 Allogeneic cancer cell-based immunotherapy
CN102036677A (en) 2008-03-20 2011-04-27 迈阿密大学 Heat shock protein GP96 vaccination and methods of using same
BRPI0911332A2 (en) 2008-04-04 2019-09-24 Calando Pharmaceuticals Inc compositions and use of epas1 inhibitors
AU2009234266B2 (en) 2008-04-11 2015-08-06 Tekmira Pharmaceuticals Corporation Site-specific delivery of nucleic acids by combining targeting ligands with endosomolytic components
AU2009236270B2 (en) 2008-04-15 2014-06-26 Government Of The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Compositions and methods for delivering inhibitory oligonucleotides
US10485879B2 (en) 2008-04-15 2019-11-26 Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services, National Institutes Of Health Plasma cell cytokine vehicle containing fusion proteins for targeted introduction of siRNA into cells and tissues
PT2274331E (en) 2008-05-02 2014-02-27 Novartis Ag Improved fibronectin-based binding molecules and uses thereof
AU2009260527A1 (en) 2008-05-30 2009-12-23 Dana-Farber Cancer Institute Inc. Methods of treating a meiotic kinesin-associated disease
US8815818B2 (en) 2008-07-18 2014-08-26 Rxi Pharmaceuticals Corporation Phagocytic cell delivery of RNAI
US20110237646A1 (en) * 2008-08-07 2011-09-29 Isis Pharmaceuticals, Inc. Modulation of transthyretin expression for the treatment of cns related disorders
AR072999A1 (en) 2008-08-11 2010-10-06 Medarex Inc HUMAN ANTIBODIES THAT JOIN GEN 3 OF LYMPHOCYTARY ACTIVATION (LAG-3) AND THE USES OF THESE
AU2009275387B2 (en) 2008-08-25 2010-07-08 Excaliard Pharmaceuticals, Inc. Antisense oligonucleotides directed against connective tissue growth factor and uses thereof
EP2166021A1 (en) * 2008-09-16 2010-03-24 Ganymed Pharmaceuticals AG Monoclonal antibodies for treatment of cancer
CN108165548B (en) 2008-09-22 2022-10-14 菲奥医药公司 Reduced size self-delivering RNAi compounds
EP3530672A1 (en) 2008-09-26 2019-08-28 Dana Farber Cancer Institute, Inc. Human anti-pd-1, pd-l1, and pd-l2 antibodies and uses thereof
EP2342356A4 (en) 2008-09-29 2012-11-21 Univ Ben Gurion Amyloid beta-peptides and methods of use thereof
GB2465748B (en) 2008-11-25 2012-04-25 Algentech Sas Plant cell transformation method
GB2465749B (en) 2008-11-25 2013-05-08 Algentech Sas Plant cell transformation method
EP2370580B1 (en) 2008-12-04 2019-09-11 CuRNA, Inc. Treatment of sirtuin 1 (sirt1) related diseases by inhibition of natural antisense transcript to sirtuin 1
CN102317458B (en) 2008-12-04 2018-01-02 库尔纳公司 Pass through treatment of the suppression of erythropoietin(EPO) (EPO) natural antisense transcript to EPO relevant diseases
WO2010065787A2 (en) 2008-12-04 2010-06-10 Curna, Inc. Treatment of tumor suppressor gene related diseases by inhibition of natural antisense transcript to the gene
EP2373690B1 (en) 2008-12-08 2015-02-11 Compugen Ltd. Antibodies specific for tmem154
WO2010078536A1 (en) 2009-01-05 2010-07-08 Rxi Pharmaceuticals Corporation Inhibition of pcsk9 through rnai
GB2467167B (en) 2009-01-26 2013-09-11 Algentech Sas Gene targeting in plants
WO2010090762A1 (en) 2009-02-04 2010-08-12 Rxi Pharmaceuticals Corporation Rna duplexes with single stranded phosphorothioate nucleotide regions for additional functionality
CA2752239C (en) 2009-02-12 2021-03-30 Opko Curna, Llc Treatment of glial cell derived neurotrophic factor (gdnf) related diseases by inhibition of natural antisense transcript to gdnf
JP5766126B2 (en) 2009-02-12 2015-08-19 クルナ・インコーポレーテッド Treatment of brain-derived neurotrophic factor (BDNF) -related diseases by suppression of natural antisense transcripts against BDNF
US8329882B2 (en) 2009-02-18 2012-12-11 California Institute Of Technology Genetic control of mammalian cells with synthetic RNA regulatory systems
EP2403946A4 (en) 2009-03-04 2012-11-14 Treatment of sirtuin 1 (sirt1) related diseases by inhibition of natural antisense transcript to sirt 1
BRPI1009232B1 (en) 2009-03-05 2022-05-03 E.R. Squibb & Sons, Llc. Isolated monoclonal antibody or an antigen-binding portion thereof, or an antibody fragment, composition comprising them, nucleic acid molecule, hybridoma and methods for preparing an anti-cadm1 antibody
CN102482677B (en) 2009-03-16 2017-10-17 库尔纳公司 Nuclear factor (red blood cell derives 2) sample 2 (NRF2) relevant disease is treated by suppressing NRF2 natural antisense transcript
CN102549159B (en) 2009-03-17 2016-08-10 库尔纳公司 By suppressing to treat the disease that DLK1 is correlated with for the natural antisense transcript of δ sample 1 congener (DLK1)
CN102356155B (en) 2009-03-18 2016-02-24 肿瘤疗法科学股份有限公司 NEIL3 peptide and comprise its vaccine
US9145555B2 (en) 2009-04-02 2015-09-29 California Institute Of Technology Integrated—ligand-responsive microRNAs
SG10201401604VA (en) 2009-04-20 2014-08-28 Oxford Biotherapeutics Ltd Antibodies Specific To Cadherin-17
EP3248618A1 (en) 2009-04-22 2017-11-29 Massachusetts Institute Of Technology Innate immune suppression enables repeated delivery of long rna molecules
EA201101572A1 (en) 2009-04-27 2012-05-30 Новартис Аг COMPOSITIONS AND METHODS OF APPLICATION OF THERAPEUTIC ANTIBODIES SPECIFIC TO THE SUB-UNIT OF BETA1 IL-12 RECEPTOR
AR076402A1 (en) 2009-04-27 2011-06-08 Novartis Ag COMPOSITIONS AND METHODS TO INCREASE MUSCLE GROWTH
DK2424987T3 (en) 2009-05-01 2018-02-26 Curna Inc TREATMENT OF HEMOGLOBIN (HBF / HBG) RELATED DISEASES BY INHIBITION OF NATURAL ANTISENSE TRANSCRIPTION TO HBF / HBG
TWI486171B (en) 2009-05-04 2015-06-01 亞培研究公司 Antibodies against nerve growth factor (ngf) with enhanced in vivo stability
ES2609655T3 (en) 2009-05-06 2017-04-21 Curna, Inc. Treatment of diseases related to tristetraproline (TTP) by inhibition of natural antisense transcript for TTP
WO2010129799A2 (en) 2009-05-06 2010-11-11 Curna, Inc. Treatment of lipid transport and metabolism gene related diseases by inhibition of natural antisense transcript to a lipid transport and metabolism gene
AU2010249046A1 (en) 2009-05-13 2011-12-01 Sea Lane Biotechnologies, Llc Neutralizing molecules to influenza viruses
EP2432881B1 (en) 2009-05-18 2017-11-15 CuRNA, Inc. Treatment of reprogramming factor related diseases by inhibition of natural antisense transcript to a reprogramming factor
EP2432499A2 (en) 2009-05-20 2012-03-28 Schering Corporation Modulation of pilr receptors to treat microbial infections
WO2010135695A2 (en) 2009-05-22 2010-11-25 Curna, Inc. TREATMENT OF TRANSCRIPTION FACTOR E3 (TFE3) and INSULIN RECEPTOR SUBSTRATE 2 (IRS2) RELATED DISEASES BY INHIBITION OF NATURAL ANTISENSE TRANSCRIPT TO TFE3
TWI507204B (en) 2009-05-26 2015-11-11 Oncotherapy Science Inc Cdc45l peptides and vaccines including the same
ES2618576T3 (en) 2009-05-28 2017-06-21 Curna, Inc. Treatment of diseases related to an antiviral gene by inhibiting a natural antisense transcript to an antiviral gene
WO2010146359A1 (en) 2009-06-15 2010-12-23 Plant Bioscience Limited Production of viral capsids
JP6128846B2 (en) 2009-06-16 2017-05-17 クルナ・インコーポレーテッド Treatment of PON1 gene-related diseases by suppression of natural antisense transcripts against paraoxonase (PON1)
WO2010148050A2 (en) 2009-06-16 2010-12-23 Curna, Inc. Treatment of collagen gene related diseases by inhibition of natural antisense transcript to a collagen gene
BRPI1015234A2 (en) 2009-06-22 2018-02-20 Medimmune Llc fc regions designed for site specific conjugation.
WO2010151671A2 (en) 2009-06-24 2010-12-29 Curna, Inc. Treatment of tumor necrosis factor receptor 2 (tnfr2) related diseases by inhibition of natural antisense transcript to tnfr2
CA2765815A1 (en) 2009-06-26 2010-12-29 Opko Curna, Llc Treatment of down syndrome gene related diseases by inhibition of natural antisense transcript to a down syndrome gene
US8394922B2 (en) 2009-08-03 2013-03-12 Medarex, Inc. Antiproliferative compounds, conjugates thereof, methods therefor, and uses thereof
CA2769665A1 (en) 2009-08-05 2011-02-10 Opko Curna, Llc Treatment of insulin gene (ins) related diseases by inhibition of natural antisense transcript to an insulin gene (ins)
US20120131701A1 (en) 2009-08-05 2012-05-24 Chromocell Corporation Improved plants, microbes, and organisms
KR101892760B1 (en) 2009-08-25 2018-08-28 큐알엔에이, 인크. Treatment of 'iq motif containing gtpase activating protein' (iqgap) related diseases by inhibition of natural antisense transcript to iqgap
US20110059111A1 (en) 2009-09-01 2011-03-10 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Mammalian receptors as targets for antibody and active vaccination therapy against mold infections
AU2010289400B2 (en) 2009-09-02 2014-10-23 Curis, Inc. Mutant smoothened and methods of using the same
WO2011029823A1 (en) 2009-09-09 2011-03-17 Novartis Ag Monoclonal antibody reactive with cd63 when expressed at the surface of degranulated mast cells
EP4089169A1 (en) 2009-10-12 2022-11-16 Larry J. Smith Methods and compositions for modulating gene expression using oligonucleotide based drugs administered in vivo or in vitro
WO2011047083A1 (en) 2009-10-13 2011-04-21 Oxford Biotherapeutics Ltd. Antibodies against epha10
CA2778442A1 (en) 2009-10-22 2011-04-28 Genentech, Inc. Methods and compositions for modulating hepsin activation of macrophage-stimulating protein
EP2357239A1 (en) 2009-10-29 2011-08-17 Universität zu Köln Methods and means for a selectable marker system in plants
WO2011051327A2 (en) 2009-10-30 2011-05-05 Novartis Ag Small antibody-like single chain proteins
WO2011051466A1 (en) 2009-11-02 2011-05-05 Novartis Ag Anti-idiotypic fibronectin-based binding molecules and uses thereof
WO2011056234A1 (en) 2009-11-06 2011-05-12 Fibrogen, Inc. Treatment for radiation-induced disorders
CN102781237A (en) * 2009-11-23 2012-11-14 天蓝制药公司 Cyclodextrin-based polymers for therapeutic delivery
CN102741294A (en) 2009-11-30 2012-10-17 霍夫曼-拉罗奇有限公司 Antibodies for treating and diagnosing tumors expressing SLC34A2 (TAT211 = SEQID 2)
US9428586B2 (en) 2009-12-01 2016-08-30 Compugen Ltd Heparanase splice variant
JP2013513588A (en) 2009-12-11 2013-04-22 ジーンコード エーエス Method for facilitating survival of neural cells using mimic or RET signaling pathway activators of GDNF family ligand (GFL)
TW201136604A (en) 2009-12-14 2011-11-01 Oncotherapy Science Inc TMEM22 peptides and vaccines including the same
NO2513310T3 (en) 2009-12-16 2018-03-31
WO2011084357A1 (en) 2009-12-17 2011-07-14 Schering Corporation Modulation of pilr to treat immune disorders
CN102686729B (en) 2009-12-18 2015-09-23 箭头研究公司 Be used for the treatment of the organic composite of HSF1 relative disease
CN102869776B (en) 2009-12-23 2017-06-23 库尔纳公司 HGF relevant diseases are treated by suppressing the natural antisense transcript of HGF (HGF)
US9068183B2 (en) 2009-12-23 2015-06-30 Curna, Inc. Treatment of uncoupling protein 2 (UCP2) related diseases by inhibition of natural antisense transcript to UCP2
CA2785173A1 (en) 2009-12-29 2011-07-28 Curna, Inc. Treatment of nuclear respiratory factor 1 (nrf1) related diseases by inhibition of natural antisense transcript to nrf1
KR101853508B1 (en) 2009-12-29 2018-06-20 큐알엔에이, 인크. TREATMENT OF TUMOR PROTEIN 63 (p63) RELATED DISEASES BY INHIBITION OF NATURAL ANTISENSE TRANSCRIPT TO p63
US8946181B2 (en) 2010-01-04 2015-02-03 Curna, Inc. Treatment of interferon regulatory factor 8 (IRF8) related diseases by inhibition of natural antisense transcript to IRF8
RU2612161C2 (en) 2010-01-06 2017-03-02 Курна, Инк. Treatment of pancreatic developmental gene related diseases by inhibition of natural antisense transcript to pancreatic developmental gene
WO2011085347A2 (en) 2010-01-11 2011-07-14 Opko Curna, Llc Treatment of sex hormone binding globulin (shbg) related diseases by inhibition of natural antisense transcript to shbg
WO2011090971A2 (en) 2010-01-19 2011-07-28 The Trustees Of Columbia University In The City Of New York Osteocalcin as a treatment for male reproductive disorders
CN102782135A (en) 2010-01-25 2012-11-14 库尔纳公司 Treatment of RNase H1 related diseases by inhibition of natural antisense transcript to RNase H1
WO2011092233A1 (en) 2010-01-29 2011-08-04 Novartis Ag Yeast mating to produce high-affinity combinations of fibronectin-based binders
MX2012009318A (en) 2010-02-10 2012-09-07 Novartis Ag Methods and compounds for muscle growth.
CA2790506A1 (en) 2010-02-22 2011-08-25 Curna, Inc. Treatment of pyrroline-5-carboxylate reductase 1 (pycr1) related diseases by inhibition of natural antisense transcript to pycr1
PE20130214A1 (en) 2010-02-23 2013-03-11 Genentech Inc COMPOSITIONS AND METHODS FOR THE DIAGNOSIS AND TREATMENT OF TUMORS
JP5778700B2 (en) 2010-02-24 2015-09-16 イミュノジェン， インコーポレイテッド Folate receptor 1 antibody and immunoconjugate and use thereof
BR112012022641A2 (en) 2010-03-11 2017-02-14 Oncotherapy Science Inc hjurp peptides and vaccines that include the same
US20110256135A1 (en) 2010-03-17 2011-10-20 Wolfgang Fraunhofer Anti-nerve growth factor (ngf) antibody compositions
EP2371864A1 (en) 2010-03-23 2011-10-05 Ganymed Pharmaceuticals AG Monoclonal antibodies for treatment of cancer
WO2011119852A1 (en) 2010-03-24 2011-09-29 Rxi Pharmaceuticals Corporation Reduced size self-delivering rnai compounds
WO2011120013A2 (en) 2010-03-26 2011-09-29 Trustees Of Dartmouth College Vista regulatory t cell mediator protein, vista binding agents and use thereof
US20150231215A1 (en) 2012-06-22 2015-08-20 Randolph J. Noelle VISTA Antagonist and Methods of Use
US10745467B2 (en) 2010-03-26 2020-08-18 The Trustees Of Dartmouth College VISTA-Ig for treatment of autoimmune, allergic and inflammatory disorders
TWI538685B (en) 2010-04-02 2016-06-21 腫瘤療法 科學股份有限公司 Ect2 peptides and vaccines including the same
TWI644675B (en) 2010-04-09 2018-12-21 可娜公司 Treatment of fibroblast growth factor 21 (fgf21) related diseases by inhibition of natural antisense transcript to fgf21
NZ602892A (en) 2010-04-13 2014-08-29 Celldex Therapeutics Inc Antibodies that bind human cd27 and uses thereof
WO2011130716A2 (en) 2010-04-16 2011-10-20 Access Pharmaceuticals, Inc. A nanostructures containing vitamin b12 for facilitated delivery of drugs across biological barriers
EA034363B1 (en) 2010-04-23 2020-01-30 Эрроухед Фармасьютикалс, Инк. PHARMACEUTICAL COMPOSITION FOR INHIBITING BETA-ENaC GENE EXPRESSION AND USE THEREOF
MX343559B (en) 2010-04-29 2016-11-10 Ionis Pharmaceuticals Inc Modulation of transthyretin expression.
MX342239B (en) 2010-05-03 2016-09-21 Genentech Inc * Compositions and methods for the diagnosis and treatment of tumor.
CN107988228B (en) 2010-05-03 2022-01-25 库尔纳公司 Treatment of Sirtuin (SIRT) related diseases by inhibition of natural antisense transcript to Sirtuin (SIRT)
WO2011140151A1 (en) 2010-05-04 2011-11-10 Dyax Corp. Antibodies against epidermal growth factor receptor (egfr)
CA2798272C (en) 2010-05-05 2019-03-26 The Board Of Trustees Of The University Of Illinois Compounds and methods of treating brain disorders
EP2566894A1 (en) 2010-05-06 2013-03-13 Novartis AG Compositions and methods of use for therapeutic low density lipoprotein - related protein 6 (lrp6) multivalent antibodies
NZ603829A (en) 2010-05-06 2015-03-27 Novartis Ag Compositions and methods of use for therapeutic low density lipoprotein -related protein 6 (lrp6) antibodies
JP5866106B2 (en) 2010-05-12 2016-02-17 コロンビア ユニヴァーシティ Method for producing enteroendocrine cells that produce and secrete insulin
TWI531370B (en) 2010-05-14 2016-05-01 可娜公司 Treatment of par4 related diseases by inhibition of natural antisense transcript to par4
GB201008720D0 (en) 2010-05-25 2010-07-07 Univ Aberdeen RxLR-leader peptides and protein translocation
DK2576783T3 (en) 2010-05-26 2018-03-12 Curna Inc TREATMENT OF ATONAL HOMOLOGY 1- (ATOH1) RELATED DISEASES BY INHIBITION OF NATURAL ANTISENCE TRANSCRIPTS AT ATOH1
CA2805024A1 (en) 2010-06-30 2012-01-05 Compugen Ltd. Polypeptides and uses thereof as a drug for treatment of multiples sclerosis, rheumatoid arthritis and other autoimmune disorders
WO2016030888A1 (en) 2014-08-26 2016-03-03 Compugen Ltd. Polypeptides and uses thereof as a drug for treatment of autoimmune disorders
NO2593547T3 (en) 2010-07-14 2018-04-14
GB201012420D0 (en) 2010-07-23 2010-09-08 Univ Erasmus Medical Ct Foetal heamoglobin inhibitor
WO2012022734A2 (en) 2010-08-16 2012-02-23 Medimmune Limited Anti-icam-1 antibodies and methods of use
MY162825A (en) 2010-08-20 2017-07-31 Novartis Ag Antibodies for epidermal growth factor receptor 3 (her3)
EP2609093B1 (en) 2010-08-24 2018-10-17 SGC Pharma Inc. Salt compound
WO2012035518A1 (en) 2010-09-17 2012-03-22 Compugen Ltd. Compositions and methods for treatment of drug resistant multiple myeloma
EP2621514B1 (en) 2010-09-28 2016-09-21 KAHR Medical (2005) Ltd Compositions and methods for treatment of hematological malignancies
US9228023B2 (en) 2010-10-01 2016-01-05 Oxford Biotherapeutics Ltd. Anti-ROR1 antibodies and methods of use for treatment of cancer
EP2625203A1 (en) 2010-10-05 2013-08-14 Novartis AG Anti-il12rbeta1 antibodies and their use in treating autoimmune and inflammatory disorders
WO2012047968A2 (en) 2010-10-05 2012-04-12 Genentech, Inc. Mutant smoothened and methods of using the same
RU2624048C2 (en) 2010-10-06 2017-06-30 Курна, Инк. Treatment of diseases associated with the sialidase 4 (neu4) gene, by gene neu4 natural antisense transcript inhibition
JP6049623B2 (en) 2010-10-22 2016-12-21 カッパーアールエヌエー，インコーポレイテッド Treatment of IDUA-related diseases by inhibition of natural antisense transcripts to α-L-iduronidase (IDUA)
KR101913232B1 (en) 2010-10-27 2018-10-30 큐알엔에이, 인크. Treatment of interferon-related developmental regulator 1(ifrd1) related diseases by inhibition of natural antisense transcript to ifrd1
EP3327125B1 (en) 2010-10-29 2020-08-05 Sirna Therapeutics, Inc. Rna interference mediated inhibition of gene expression using short interfering nucleic acids (sina)
US20140134181A1 (en) 2010-11-05 2014-05-15 Kenneth E. Lipson Treatment Method For Lung Remodeling Diseases
JP6071893B2 (en) 2010-11-23 2017-02-01 カッパーアールエヌエー，インコーポレイテッド Treatment of NANOG-related diseases by inhibition of natural antisense transcripts to NANOG
US20130245233A1 (en) 2010-11-24 2013-09-19 Ming Lei Multispecific Molecules
MX365647B (en) 2011-02-02 2019-06-10 Excaliard Pharmaceuticals Inc Method of treating keloids or hypertrophic scars using antisense compounds targeting connective tissue growth factor (ctgf).
WO2012109495A1 (en) 2011-02-09 2012-08-16 Metabolic Solutions Development Company, Llc Cellular targets of thiazolidinediones
WO2012119989A2 (en) 2011-03-04 2012-09-13 Oryzon Genomics, S.A. Methods and antibodies for the diagnosis and treatment of cancer
WO2012122313A2 (en) 2011-03-08 2012-09-13 Access Pharmaceuticals, Inc. Targeted nanocarrier systems for delivery of actives across biological membranes
SI2694106T1 (en) 2011-04-01 2018-04-30 Immunogen, Inc. Methods for increasing efficacy of folr1 cancer therapy
CN105886506A (en) 2011-04-13 2016-08-24 Isis制药公司 Antisense modulation of PTP1B expression
WO2012140627A1 (en) 2011-04-15 2012-10-18 Compugen Ltd. Polypeptides and polynucleotides, and uses thereof for treatment of immune related disorders and cancer
CN103620036B (en) 2011-06-09 2016-12-21 库尔纳公司 FXN relevant disease is treated by the natural antisense transcript of suppression Frataxin (FXN)
WO2012174476A2 (en) 2011-06-16 2012-12-20 Isis Pharmaceuticals, Inc. Antisense modulation of fibroblast growth factor receptor 4 expression
NZ618503A (en) 2011-06-28 2016-03-31 Oxford Biotherapeutics Ltd Antibodies to adp-ribosyl cyclase 2
PT2726101T (en) 2011-06-30 2018-11-21 Genzyme Corp Inhibitors of t-cell activation
WO2013001517A1 (en) 2011-06-30 2013-01-03 Compugen Ltd. Polypeptides and uses thereof for treatment of autoimmune disorders and infection
HUE040276T2 (en) 2011-07-01 2019-02-28 Novartis Ag Method for treating metabolic disorders
US9238689B2 (en) 2011-07-15 2016-01-19 Morpho Sys AG Antibodies that are cross-reactive for macrophage migration inhibitory factor (MIF) and D-dopachrome tautomerase (D-DT)
EP2734232B1 (en) 2011-07-19 2017-11-01 Philogen S.p.A. Sequential anti-ctla4 and targeted il-2 therapy
CA2842860A1 (en) 2011-07-28 2013-01-31 Sea Lane Biotechnologies, Llc Sur-binding proteins
EP3521432A1 (en) 2011-09-02 2019-08-07 Arrowhead Pharmaceuticals, Inc. Organic compositions to treat hsf1-related diseases
UY34317A (en) 2011-09-12 2013-02-28 Genzyme Corp T cell antireceptor antibody (alpha) / ß
WO2013043569A1 (en) 2011-09-20 2013-03-28 Vical Incorporated Synergistic anti-tumor efficacy using alloantigen combination immunotherapy
KR101840512B1 (en) 2011-09-20 2018-03-20 아이오니스 파마수티컬즈, 인코포레이티드 Antisense modulation of gcgr expression
US20130085139A1 (en) 2011-10-04 2013-04-04 Royal Holloway And Bedford New College Oligomers
WO2013063313A1 (en) 2011-10-25 2013-05-02 Isis Pharmaceuticals, Inc. Antisense modulation of gccr expression
CA3122778A1 (en) 2011-10-28 2013-05-02 Oncotherapy Science, Inc. Topk peptides and vaccines including the same
EA201491107A1 (en) 2011-12-05 2014-11-28 Новартис Аг ANTIBODIES TO THE RECEPTOR EPIDERMAL GROWTH FACTOR 3 (HER3), DIRECTED TO DOMAIN II HER3
CN104159924B (en) 2011-12-05 2018-03-16 诺华股份有限公司 The antibody of EGF-R ELISA 3 (HER3)
US9393320B2 (en) 2011-12-07 2016-07-19 Universidade Do Minho Liposomes and its production method
EP2793940B1 (en) 2011-12-22 2018-11-14 i2 Pharmaceuticals, Inc. Surrogate binding proteins
ES2721882T3 (en) 2011-12-23 2019-08-06 Pfizer Constant regions of genetically engineered antibody for site-specific conjugation and procedures and uses thereof
CA2860676A1 (en) 2012-01-09 2013-07-18 Novartis Ag Organic compositions to treat beta-catenin-related diseases
SG2014008304A (en) 2012-02-01 2014-06-27 Compugen Ltd C10rf32 antibodies, and uses thereof for treatment of cancer
AU2013221873B2 (en) 2012-02-13 2016-11-17 Bristol-Myers Squibb Company Enediyne compounds, conjugates thereof, and uses and methods therefor
US10080805B2 (en) 2012-02-24 2018-09-25 Purdue Research Foundation Cholecystokinin B receptor targeting for imaging and therapy
ES2694592T3 (en) 2012-03-15 2018-12-21 Curna, Inc. Treatment of diseases related to brain-derived neurotrophic factor (BDNF) by inhibition of the natural antisense transcript of BDNF
ES2700742T3 (en) 2012-03-16 2019-02-19 Merck Patent Gmbh Lipids amino acids
SG11201405552VA (en) 2012-03-16 2014-10-30 Merck Patent Gmbh Targeting aminoacid lipids
US20150079100A1 (en) 2012-03-23 2015-03-19 Bristol-Myers Squibb Company Methods of treatments using ctla-4 antibodies
US20140080175A1 (en) 2012-03-29 2014-03-20 Endocyte, Inc. Processes for preparing tubulysin derivatives and conjugates thereof
US9181572B2 (en) 2012-04-20 2015-11-10 Abbvie, Inc. Methods to modulate lysine variant distribution
WO2013167153A1 (en) 2012-05-09 2013-11-14 Ganymed Pharmaceuticals Ag Antibodies useful in cancer diagnosis
CN108524919A (en) 2012-05-17 2018-09-14 延伸生物科学股份有限公司 carrier for improved drug delivery
WO2013176754A1 (en) 2012-05-24 2013-11-28 Abbvie Inc. Novel purification of antibodies using hydrophobic interaction chromatography
CN104334576B (en) 2012-06-04 2019-02-19 诺华股份有限公司 Site-specific labeling's method and resulting molecule
US9890215B2 (en) 2012-06-22 2018-02-13 King's College London Vista modulators for diagnosis and treatment of cancer
AR091649A1 (en) 2012-07-02 2015-02-18 Bristol Myers Squibb Co OPTIMIZATION OF ANTIBODIES THAT FIX THE LYMPHOCYTE ACTIVATION GEN 3 (LAG-3) AND ITS USES
CA3137438A1 (en) 2012-08-31 2014-03-06 Immunogen, Inc. Diagnostic assays and kits for detection of folate receptor 1
CN109793893B (en) 2012-09-07 2023-05-26 达特茅斯大学理事会 VISTA modulators for diagnosis and treatment of cancer
US20160136159A1 (en) 2012-09-17 2016-05-19 Chemedest Ltd. Method for Treating Peripheral Neuropathy
US20140094432A1 (en) 2012-10-02 2014-04-03 Cerulean Pharma Inc. Methods and systems for polymer precipitation and generation of particles
SG11201502896XA (en) 2012-10-16 2015-05-28 Endocyte Inc Drug delivery conjugates containing unnatural amino acids and methods for using
ES2662020T3 (en) 2012-10-22 2018-04-05 Fountain Biopharma Inc. Antibodies against interleukin-6 and its uses
WO2014071406A1 (en) 2012-11-05 2014-05-08 Pronai Therapeutics, Inc. Methods of using biomarkers for the treatment of cancer by modulation of bcl2|expression
AU2013343099A1 (en) 2012-11-09 2015-05-14 Pfizer Inc. Platelet-derived growth factor B specific antibodies and compositions and uses thereof
MY174820A (en) 2012-12-18 2020-05-17 Novartis Ag Stabilized insulin-like growth factor polypeptides
PT2953976T (en) 2013-02-08 2021-06-23 Novartis Ag Specific sites for modifying antibodies to make immunoconjugates
PT2953969T (en) 2013-02-08 2019-12-03 Novartis Ag Anti-il-17a antibodies and their use in treating autoimmune and inflammatory disorders
WO2014124258A2 (en) 2013-02-08 2014-08-14 Irm Llc Specific sites for modifying antibodies to make immunoconjugates
EP2956173B1 (en) 2013-02-14 2017-03-29 Bristol-Myers Squibb Company Tubulysin compounds, methods of making and use
US9498532B2 (en) 2013-03-13 2016-11-22 Novartis Ag Antibody drug conjugates
EP2970375A1 (en) 2013-03-14 2016-01-20 AbbVie Inc. Low acidic species compositions and methods for producing the same using displacement chromatography
CA2926301A1 (en) 2013-03-14 2014-10-02 Abbvie Inc. Low acidic species compositions and methods for producing and using the same
EP2970479B1 (en) 2013-03-14 2019-04-24 Novartis AG Antibodies against notch 3
WO2014152497A2 (en) 2013-03-15 2014-09-25 The Trustees Of Columbia University In The City Of New York Osteocalcin as a treatment for cognitive disorders
US9308236B2 (en) 2013-03-15 2016-04-12 Bristol-Myers Squibb Company Macrocyclic inhibitors of the PD-1/PD-L1 and CD80(B7-1)/PD-L1 protein/protein interactions
EP3514178A1 (en) 2013-03-15 2019-07-24 Novartis AG Antibody drug conjugates
ES2862125T3 (en) 2013-06-13 2021-10-07 Antisense Therapeutics Ltd Combination therapy for acromegaly
EP4001275A1 (en) 2013-06-26 2022-05-25 Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt GmbH (s)-enantiomer of mepazine as paracaspase (malt1) inhibitor for the treatment of cancer
EP3470420A1 (en) 2013-08-14 2019-04-17 Institute Of Genetics And Developmental Biology Methods of modulating seed and organ size in plants
IL293871A (en) 2013-08-30 2022-08-01 Immunogen Inc Antibodies and assays for detection of folate receptor 1
CA2922838A1 (en) 2013-09-05 2015-03-12 Sarepta Therapeutics, Inc. Antisense-induced exon2 inclusion in acid alpha-glucosidase
WO2015036643A2 (en) 2013-09-13 2015-03-19 Sierra Jiménez Angels Marker for predicting metastasis of breast cancer
US10036020B2 (en) 2013-09-19 2018-07-31 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Compositions and methods for inhibiting JC virus (JCV)
WO2015050959A1 (en) 2013-10-01 2015-04-09 Yale University Anti-kit antibodies and methods of use thereof
US20160271265A1 (en) 2013-10-02 2016-09-22 Novartis Ag Insulin-like growth factor mimetics for use in therapy
EA036927B1 (en) 2013-10-11 2021-01-15 Оксфорд Биотерепьютикс Лтд Conjugated antibodies against ly75 for the treatment of cancer
GB201319876D0 (en) 2013-11-11 2013-12-25 Plant Bioscience Ltd Methods of modulating seed and organ size in plants
WO2015073580A1 (en) 2013-11-13 2015-05-21 Pfizer Inc. Tumor necrosis factor-like ligand 1a specific antibodies and compositions and uses thereof
EP3071971B1 (en) 2013-11-19 2019-04-24 Purdue Research Foundation Patient selection method for inflammation
UY35874A (en) 2013-12-12 2015-07-31 Novartis Ag A PROCESS FOR THE PREPARATION OF A COMPOSITION OF PEGILATED PROTEINS
US11014987B2 (en) 2013-12-24 2021-05-25 Janssen Pharmaceutics Nv Anti-vista antibodies and fragments, uses thereof, and methods of identifying same
CA2935378C (en) 2013-12-24 2023-04-18 Janssen Pharmaceutica Nv Anti-vista antibodies and fragments
WO2015109212A1 (en) 2014-01-17 2015-07-23 Pfizer Inc. Anti-il-2 antibodies and compositions and uses thereof
WO2015116902A1 (en) 2014-01-31 2015-08-06 Genentech, Inc. G-protein coupled receptors in hedgehog signaling
JP6736467B2 (en) 2014-02-04 2020-08-05 ジェネンテック， インコーポレイテッド Smoothing mutant and method of using the same
KR20160125515A (en) 2014-03-12 2016-10-31 노파르티스 아게 Specific sites for modifying antibodies to make immunoconjugates
WO2015171918A2 (en) 2014-05-07 2015-11-12 Louisiana State University And Agricultural And Mechanical College Compositions and uses for treatment thereof
GB201408623D0 (en) 2014-05-15 2014-07-02 Santaris Pharma As Oligomers and oligomer conjugates
RS59643B1 (en) 2014-06-06 2020-01-31 Bristol Myers Squibb Co Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof
MX2016016310A (en) 2014-06-11 2017-10-20 A Green Kathy Use of vista agonists and antagonists to suppress or enhance humoral immunity.
US20170291939A1 (en) 2014-06-25 2017-10-12 Novartis Ag Antibodies specific for il-17a fused to hyaluronan binding peptide tags
EP3160503B1 (en) 2014-06-26 2021-02-17 The Trustees of Columbia University in the City of New York Inhibition of serotonin expression in gut enteroendocrine cells results in conversion to insulin-positive cells
US20170226552A1 (en) 2014-07-03 2017-08-10 Abbvie Inc. Methods for modulating protein glycosylation profiles of recombinant protein therapeutics using cobalt
US20160185848A1 (en) 2014-07-09 2016-06-30 Abbvie Inc. Methods for modulating the glycosylation profile of recombinant proteins using sugars
ES2729202T3 (en) 2014-07-16 2019-10-30 Dana Farber Cancer Inst Inc Et Al Inhibition of HER3 in low grade serous ovarian cancers
US10786578B2 (en) 2014-08-05 2020-09-29 Novartis Ag CKIT antibody drug conjugates
EP4108256A1 (en) 2014-08-11 2022-12-28 University of Massachusetts Anti-ospa antibodies and methods of use
PE20170903A1 (en) 2014-08-12 2017-07-12 Novartis Ag DRUG CONJUGATES WITH ANTI-CDH6 ANTIBODIES
WO2016033424A1 (en) 2014-08-29 2016-03-03 Genzyme Corporation Methods for the prevention and treatment of major adverse cardiovascular events using compounds that modulate apolipoprotein b
EP2993174A1 (en) 2014-09-08 2016-03-09 Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt GmbH Pyrazolopyridine derivatives and their use in therapy
US9732119B2 (en) 2014-10-10 2017-08-15 Bristol-Myers Squibb Company Immunomodulators
US9789197B2 (en) 2014-10-22 2017-10-17 Extend Biosciences, Inc. RNAi vitamin D conjugates
WO2016065052A1 (en) 2014-10-22 2016-04-28 Extend Biosciences, Inc. Insulin vitamin d conjugates
JP6946182B2 (en) 2014-10-22 2021-10-06 エクステンド バイオサイエンシズ インコーポレーテッドＥｘｔｅｎｄ Ｂｉｏｓｃｉｅｎｃｅｓ， Ｉｎｃ Therapeutic Vitamin D Conjugate
US10077287B2 (en) 2014-11-10 2018-09-18 Bristol-Myers Squibb Company Tubulysin analogs and methods of making and use
EP3217982A1 (en) 2014-11-10 2017-09-20 Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) Spiropyrazine derivatives as inhibitors of non-apoptotic regulated cell-death
JOP20200092A1 (en) 2014-11-10 2017-06-16 Alnylam Pharmaceuticals Inc HEPATITIS B VIRUS (HBV) iRNA COMPOSITIONS AND METHODS OF USE THEREOF
US9856292B2 (en) 2014-11-14 2018-01-02 Bristol-Myers Squibb Company Immunomodulators
CA2967188A1 (en) 2014-11-14 2016-05-19 Novartis Ag Antibody drug conjugates
EP3226889A4 (en) 2014-11-19 2018-11-21 The Trustees of Columbia University in the City of New York Osteocalcin as a treatment for frailty associated with aging
CN113773388A (en) 2014-11-21 2021-12-10 百时美施贵宝公司 anti-CD 73 antibodies and uses thereof
CN107250157B (en) 2014-11-21 2021-06-29 百时美施贵宝公司 Antibodies comprising modified heavy chain constant regions
JP6622814B2 (en) 2014-11-25 2019-12-18 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Novel PD-L1 binding polypeptides for imaging
BR112017010414A2 (en) 2014-11-25 2018-05-15 Bristol-Myers Squibb Company methods and compositions for 18f radiolabeling of biological substances
US20170269092A1 (en) 2014-12-02 2017-09-21 Cemm - Forschungszentrum Fuer Molekulare Medizin Gmbh Anti-mutant calreticulin antibodies and their use in the diagnosis and therapy of myeloid malignancies
JP2018505911A (en) 2014-12-05 2018-03-01 イミュネクスト，インコーポレーテッド Identification of VSIG8 as a putative VISTA receptor and its use to produce a VISTA / VSIG8 modulator
ES2784900T3 (en) 2014-12-12 2020-10-01 Massachusetts Gen Hospital Treatment of brain metastases from breast cancer
US9861680B2 (en) 2014-12-18 2018-01-09 Bristol-Myers Squibb Company Immunomodulators
CA2971542A1 (en) 2014-12-19 2016-06-23 Regenesance B.V. Antibodies that bind human c6 and uses thereof
US9944678B2 (en) 2014-12-19 2018-04-17 Bristol-Myers Squibb Company Immunomodulators
TWI708786B (en) 2014-12-23 2020-11-01 美商必治妥美雅史谷比公司 Antibodies to tigit
MX2017009144A (en) 2015-01-14 2017-11-22 Bristol Myers Squibb Co Heteroarylene-bridged benzodiazepine dimers, conjugates thereof, and methods of making and using.
TW201632202A (en) 2015-01-30 2016-09-16 諾華公司 Treatment of breast cancer
US20160222060A1 (en) 2015-02-04 2016-08-04 Bristol-Myers Squibb Company Immunomodulators
WO2016144773A1 (en) 2015-03-06 2016-09-15 Abbvie Inc. Arabinosylated glycoproteins
US20180044429A1 (en) 2015-03-09 2018-02-15 Celldex Therapeutics, Inc. Cd27 agonists
MA41795A (en) 2015-03-18 2018-01-23 Sarepta Therapeutics Inc EXCLUSION OF AN EXON INDUCED BY ANTISENSE COMPOUNDS IN MYOSTATIN
US9809625B2 (en) 2015-03-18 2017-11-07 Bristol-Myers Squibb Company Immunomodulators
EP3280705B1 (en) 2015-04-10 2021-07-21 Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) Pyrone derivatives for use as antiviral agents
AU2016257724B2 (en) 2015-05-01 2021-02-25 Allysta Pharmaceuticals, Inc. Adiponectin peptidomimetics for treating ocular disorders
FI3447075T3 (en) 2015-05-15 2023-11-07 Massachusetts Gen Hospital Antagonistic anti-tumor necrosis factor receptor superfamily antibodies
EP3297676A2 (en) 2015-05-22 2018-03-28 Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) Combination of trpm8-agonist and nachr-agonist for treatment of obesity and related disorders and for weight reduction
CN107847444A (en) * 2015-05-26 2018-03-27 通用医疗公司 Liposome nanometer construct and its preparation and application
HUE061253T2 (en) 2015-05-29 2023-06-28 Bristol Myers Squibb Co Antibodies against ox40 and uses thereof
MA50829A (en) 2015-06-01 2018-04-11 Sarepta Therapeutics Inc EXCLUSION OF EXON INDUCED BY ANTISEN TECHNOLOGY IN TYPE VII COLLAGEN
EP3310813A1 (en) 2015-06-17 2018-04-25 Novartis AG Antibody drug conjugates
CN107922497B (en) 2015-06-24 2022-04-12 詹森药业有限公司 anti-VISTA antibodies and fragments
MX2017016502A (en) 2015-06-29 2018-03-12 Univ Rockefeller Antibodies to cd40 with enhanced agonist activity.
EP3971211A1 (en) 2015-07-13 2022-03-23 Compugen Ltd. Hide1 compositions and methods
WO2017015619A1 (en) 2015-07-23 2017-01-26 The Regents Of The University Of California Antibodies to coagulation factor xia and uses thereof
US9862760B2 (en) 2015-09-16 2018-01-09 Novartis Ag Polyomavirus neutralizing antibodies
WO2017049149A1 (en) 2015-09-17 2017-03-23 Immunogen, Inc. Therapeutic combinations comprising anti-folr1 immunoconjugates
RU2638457C2 (en) 2015-09-28 2017-12-13 Общество С Ограниченной Ответственностью "Онкомакс" Antibodies specifically binding type 1 receptor of fibroblast growth factor, antibodies application for oncological disease treatment, method for antibodies production
WO2017058881A1 (en) 2015-09-28 2017-04-06 The Trustees Of Columbia University In The City Of New York Use of pentoxifylline with immune checkpoint-blockade therapies for the treatment of melanoma
US11266730B2 (en) 2015-09-29 2022-03-08 The General Hospital Corporation Methods of treating and diagnosing disease using biomarkers for BCG therapy
WO2017062835A2 (en) 2015-10-09 2017-04-13 Sarepta Therapeutics, Inc. Compositions and methods for treating duchenne muscular dystrophy and related disorders
US10138298B2 (en) 2015-10-23 2018-11-27 The Regents Of The University Of California Anti-IL-2 antibodies and compositions and uses thereof
MA44334A (en) 2015-10-29 2018-09-05 Novartis Ag ANTIBODY CONJUGATES INCLUDING A TOLL-TYPE RECEPTOR AGONIST
ES2938883T3 (en) 2015-11-05 2023-04-17 Los Angeles Childrens Hospital Oligo antisense for use in the treatment of acute myeloid leukemia
CN106699889A (en) 2015-11-18 2017-05-24 礼进生物医药科技（上海）有限公司 PD-1 resisting antibody and treatment application thereof
CN108738324B (en) 2015-11-19 2022-06-21 百时美施贵宝公司 Anti-glucocorticoid-induced tumor necrosis factor receptor (GITR) antibodies and uses thereof
EP3383903A1 (en) 2015-11-30 2018-10-10 Bristol-Myers Squibb Company Anti human ip-10 antibodies and their uses
WO2017095823A1 (en) 2015-11-30 2017-06-08 The Regents Of The University Of California Tumor-specific payload delivery and immune activation using a human antibody targeting a highly specific tumor cell surface antigen
WO2017125897A1 (en) 2016-01-21 2017-07-27 Novartis Ag Multispecific molecules targeting cll-1
WO2017136558A1 (en) 2016-02-04 2017-08-10 Curis, Inc. Mutant smoothened and methods of using the same
TWI756204B (en) 2016-02-12 2022-03-01 比利時商楊森製藥公司 Anti-vista antibodies and fragments, uses thereof, and methods of identifying same
RU2018131123A (en) 2016-02-17 2020-03-17 Новартис Аг ANTIBODIES TO TGF-BETA2
EA201891925A1 (en) 2016-03-04 2019-02-28 Зэ Рокфеллер Юниверсити ANTIBODIES TO CD40 WITH STRENGTHENED AGONISTIC ACTIVITY
AU2017228470A1 (en) 2016-03-04 2018-08-30 Bristol-Myers Squibb Company Combination therapy with anti-CD73 antibodies
US10143746B2 (en) 2016-03-04 2018-12-04 Bristol-Myers Squibb Company Immunomodulators
US10358463B2 (en) 2016-04-05 2019-07-23 Bristol-Myers Squibb Company Immunomodulators
SG11201808633RA (en) 2016-04-15 2018-10-30 Immunext Inc Anti-human vista antibodies and use thereof
MX2018012695A (en) 2016-04-18 2019-06-20 Sarepta Therapeutics Inc Antisense oligomers and methods of using the same for treating diseases associated with the acid alpha-glucosidase gene.
MA44723A (en) 2016-04-18 2019-02-27 Celldex Therapeutics Inc HUMAN CD40 BINDING AGONIST ANTIBODIES AND THEIR USES
CN109072232B (en) 2016-04-22 2022-11-15 生物技术公司 Method for providing single-stranded RNA
WO2017201111A1 (en) 2016-05-19 2017-11-23 Bristol-Myers Squibb Company Pet-imaging immunomodulators
WO2017210335A1 (en) 2016-06-01 2017-12-07 Bristol-Myers Squibb Company Imaging methods using 18f-radiolabeled biologics
US11344639B2 (en) 2016-06-01 2022-05-31 Bristol-Myers Squibb Company PET imaging with PD-L1 binding polypeptides
US20180002417A1 (en) 2016-06-15 2018-01-04 Celimmune Llc Methods and Compositions for the Treatment of Celiac Disease, Non-Celiac Gluten Sensitivity, and Refractory Celiac Disease
EP3260542A1 (en) 2016-06-20 2017-12-27 Algentech Protein production in plant cells
PE20190418A1 (en) 2016-07-14 2019-03-19 Bristol Myers Squibb Co ANTIBODIES AGAINST PROTEIN 3 CONTAINING THE MUCIN AND IMMUNOGLOBULIN T-LYMPHOCYTE DOMAIN (TIM3) AND THEIR USES
ES2902179T3 (en) 2016-08-19 2022-03-25 Bristol Myers Squibb Co Seco-cyclopropapyrroloindole compounds, antibody-drug conjugates thereof, and methods of making and use
US10981976B2 (en) 2016-08-31 2021-04-20 University Of Rochester Human monoclonal antibodies to human endogenous retrovirus K envelope (HERV-K) and use thereof
EP3305781A1 (en) 2016-10-07 2018-04-11 Deutsches Krebsforschungszentrum Chemical substances which inhibit the enzymatic activity of human kallikrein-related peptidase 6 (klk6)
CA3040189A1 (en) 2016-10-13 2018-04-19 Massachusetts Institute Of Technology Antibodies that bind zika virus envelope protein and uses thereof
US10538556B2 (en) 2016-11-07 2020-01-21 Colorado State University Research Foundation Anti-HIV peptides
WO2018085750A2 (en) 2016-11-07 2018-05-11 Bristol-Myers Squibb Company Immunomodulators
US11434301B2 (en) 2016-11-11 2022-09-06 The Regents Of The University Of California Anti-CD46 antibodies and methods of use
PL3565828T3 (en) 2017-01-05 2022-04-04 Kahr Medical Ltd. A sirp1 alpha-41bbl fusion protein and methods of use thereof
AU2018205888B2 (en) 2017-01-05 2021-09-02 Kahr Medical Ltd. A PD1-41BBL fusion protein and methods of use thereof
JP7252526B2 (en) 2017-01-23 2023-04-05 スチョー アルファマブ カンパニー リミテッド PD-L1 binding polypeptide or compound
JOP20190187A1 (en) 2017-02-03 2019-08-01 Novartis Ag Anti-ccr7 antibody drug conjugates
SG11201906947SA (en) 2017-02-17 2019-08-27 Bristol Myers Squibb Co Antibodies to alpha-synuclein and uses thereof
GB201703876D0 (en) 2017-03-10 2017-04-26 Berlin-Chemie Ag Pharmaceutical combinations
WO2018185618A1 (en) 2017-04-03 2018-10-11 Novartis Ag Anti-cdh6 antibody drug conjugates and anti-gitr antibody combinations and methods of treatment
TWI788340B (en) 2017-04-07 2023-01-01 美商必治妥美雅史谷比公司 Anti-icos agonist antibodies and uses thereof
US11324820B2 (en) 2017-04-18 2022-05-10 Alnylam Pharmaceuticals, Inc. Methods for the treatment of subjects having a hepatitis b virus (HBV) infection
AR111651A1 (en) 2017-04-28 2019-08-07 Novartis Ag CONJUGATES OF ANTIBODIES THAT INCLUDE TOLL TYPE RECEIVER AGONISTS AND COMBINATION THERAPIES
WO2018209288A1 (en) 2017-05-12 2018-11-15 Massachusetts Institute Of Technology Argonaute protein-double stranded rna complexes and uses related thereto
CN111094335B (en) 2017-05-15 2022-08-23 罗切斯特大学 Broadly neutralizing anti-influenza monoclonal antibodies and uses thereof
CN116333129A (en) 2017-05-25 2023-06-27 百时美施贵宝公司 Antibodies comprising modified heavy chain constant regions
US20230137562A1 (en) 2017-06-07 2023-05-04 Adrx, Inc. Tau aggregation inhibitors
WO2018233333A1 (en) 2017-06-23 2018-12-27 苏州博聚华生物医药科技有限公司 Monoclonal antibody of targeted human tumor stem cells and application of monoclonal antibody
WO2018237153A1 (en) 2017-06-23 2018-12-27 Bristol-Myers Squibb Company Immunomodulators acting as antagonists of pd-1
EP3668886A2 (en) 2017-08-18 2020-06-24 Adrx, Inc. Tau aggregation peptide inhibitors
CA3074128A1 (en) 2017-08-28 2019-03-07 Shanghai Yile Biotechnology Co., Ltd. Polypeptide and antibody bound to polypeptide
JP7257393B2 (en) 2017-10-03 2023-04-13 ブリストル－マイヤーズ スクイブ カンパニー Immunomodulator
WO2019075090A1 (en) 2017-10-10 2019-04-18 Tilos Therapeutics, Inc. Anti-lap antibodies and uses thereof
WO2019079637A2 (en) 2017-10-18 2019-04-25 Sarepta Therapeutics, Inc. Antisense oligomer compounds
CN117106096A (en) 2017-10-26 2023-11-24 盛禾(中国)生物制药有限公司 Novel recombinant fusion proteins, their preparation and use
CN111542544A (en) 2017-11-01 2020-08-14 百时美施贵宝公司 Immunostimulatory antibodies for the treatment of cancer
AU2018361819A1 (en) 2017-11-02 2020-04-16 Oxford Biotherapeutics Ltd Antibodies and methods of use
US11433132B2 (en) 2017-12-01 2022-09-06 Novartis Ag Polyomavirus neutralizing antibodies
MX2020005662A (en) 2017-12-01 2020-08-20 Pfizer Anti-cxcr5 antibodies and compositions and uses thereof.
EP4295915A2 (en) 2017-12-20 2023-12-27 Harbour Biomed (Shanghai) Co., Ltd Antibodies binding ctla-4 and uses thereof
JP2021507944A (en) 2017-12-21 2021-02-25 グリアファーム エスエー Compositions and treatments for neuropathy, including motor neuron disease
EP3728201A1 (en) 2017-12-21 2020-10-28 Gliapharm SA Compositions and methods of treatment for neurological disorders comprising a dementia
KR20200103761A (en) 2017-12-27 2020-09-02 브리스톨-마이어스 스큅 컴퍼니 Anti-CD40 antibody and uses thereof
CN111886255A (en) 2018-01-12 2020-11-03 百时美施贵宝公司 anti-TIM 3 antibodies and uses thereof
US20210363172A1 (en) 2018-03-15 2021-11-25 Biontech Rna Pharmaceuticals Gmbh 5'-cap-trinucleotide- or higher oligonucleotide compounds and their use in stabilizing rna, expressing proteins in therapy
TW202003565A (en) 2018-03-23 2020-01-16 美商必治妥美雅史谷比公司 Antibodies against MICA and/or MICB and uses thereof
US20220064274A1 (en) 2018-03-26 2022-03-03 Shanghai Yile Biotechnology Co., Ltd. Use of probdnf regulator in b cell-related diseases
WO2019185129A1 (en) 2018-03-27 2019-10-03 The University Court Of The University Of Glasgow Bacterial pathogen derived resistance in plants
AU2019242451A1 (en) 2018-03-29 2020-11-12 Pfizer Inc. LFA3 variants and compositions and uses thereof
JOP20200240A1 (en) 2018-04-02 2020-09-27 Bristol Myers Squibb Co Anti-trem-1 antibodies and uses thereof reference to sequence listing submitted electronically via efs-web
AU2019247490A1 (en) 2018-04-06 2020-10-22 Children's Medical Center Corporation Compositions and methods for somatic cell reprogramming and modulating imprinting
KR20200142542A (en) 2018-04-12 2020-12-22 브리스톨-마이어스 스큅 컴퍼니 Anticancer combination therapy with CD73 antagonist antibody and PD-1/PD-L1 axis antagonist antibody
MX2020010913A (en) 2018-04-17 2021-01-08 Celldex Therapeutics Inc Anti-cd27 and anti-pd-l1 antibodies and bispecific constructs.
US20210179602A1 (en) 2018-04-20 2021-06-17 Iomx Therapeutics Ag A 5-thiazolecarboxamide kinase inhibitor and uses thereof
JP7402541B2 (en) 2018-05-03 2023-12-21 ユニバーシティ オブ ロチェスター Anti-influenza neuraminidase monoclonal antibody and its use
WO2019229699A1 (en) 2018-05-31 2019-12-05 Novartis Ag Hepatitis b antibodies
EP3802611A2 (en) 2018-06-01 2021-04-14 Novartis AG Binding molecules against bcma and uses thereof
GB201809746D0 (en) 2018-06-14 2018-08-01 Berlin Chemie Ag Pharmaceutical combinations
WO2020014298A1 (en) 2018-07-10 2020-01-16 Rush University Medical Center Use of immunomodulators to control infection and stimulate healing in normal and diabetic wounds
CA3104780A1 (en) 2018-07-11 2020-01-16 Kahr Medical Ltd. Sirpalpha-4-1bbl variant fusion protein and methods of use thereof
CN112533954A (en) 2018-08-08 2021-03-19 宜明昂科生物医药技术（上海）有限公司 Recombinant bifunctional protein targeting CD47 and HER2
EA202190528A1 (en) 2018-08-13 2021-04-23 Элнилэм Фармасьютикалз, Инк. COMPOSITIONS OF HEPATITIS B VIRUS (HBV) dsRNA AGENTS AND METHODS OF THEIR APPLICATION
JP2022508015A (en) 2018-09-07 2022-01-19 ファイザー・インク Anti-αvβ8 antibody, composition and use thereof
WO2020053742A2 (en) 2018-09-10 2020-03-19 Novartis Ag Anti-hla-hbv peptide antibodies
WO2020076969A2 (en) 2018-10-10 2020-04-16 Tilos Therapeutics, Inc. Anti-lap antibody variants and uses thereof
WO2020084005A1 (en) 2018-10-23 2020-04-30 Myelopro Diagnostics And Research Gmbh Compounds targeting mutant calreticulin
EP3643713A1 (en) 2018-10-23 2020-04-29 iOmx Therapeutics AG Heterocyclic kinase inhibitors and uses thereof
EP3876989A4 (en) 2018-11-09 2022-12-07 University of Massachusetts Anti-cfae antibodies and methods of use
PE20211284A1 (en) 2018-11-16 2021-07-19 Bristol Myers Squibb Co ANTI-NKG2A ANTIBODIES AND USES OF THEM
WO2020112781A1 (en) 2018-11-28 2020-06-04 Bristol-Myers Squibb Company Antibodies comprising modified heavy constant regions
WO2020128863A1 (en) 2018-12-19 2020-06-25 Novartis Ag Anti-tnf-alpha antibodies
MX2021007274A (en) 2018-12-21 2021-07-15 Ose Immunotherapeutics Bifunctional anti-pd-1/sirpa molecule.
CN113614109A (en) 2018-12-21 2021-11-05 Ose免疫疗法公司 Bifunctional anti-PD-1/IL-7 molecules
BR112021011900A2 (en) 2018-12-21 2021-09-08 Novartis Ag ANTIBODIES TO PMEL17 AND CONJUGATES THEREOF
US11352430B2 (en) 2018-12-21 2022-06-07 Ose Immunotherapeutics Humanized anti-human-PD-1 antibody and its use in cancer treatment
JP2022515223A (en) 2018-12-21 2022-02-17 オーエスイー・イミュノセラピューティクス Bifunctional molecule for human PD-1
WO2020132378A2 (en) 2018-12-22 2020-06-25 Gliapharm Sa Compositions and methods of treatment for neurological disorders comprising depression
CN109762067B (en) 2019-01-17 2020-02-28 北京天广实生物技术股份有限公司 Antibodies that bind human Claudin18.2 and uses thereof
WO2020165374A1 (en) 2019-02-14 2020-08-20 Ose Immunotherapeutics Bifunctional molecule comprising il-15ra
CA3132959A1 (en) 2019-03-08 2020-09-17 AbTis Co., Ltd. Site-specific antibody conjugation and antibody-drug conjugate as specific embodiment thereof
WO2020206063A1 (en) 2019-04-03 2020-10-08 Genzyme Corporation Anti-alpha beta tcr binding polypeptides with reduced fragmentation
WO2020236841A2 (en) 2019-05-20 2020-11-26 Novartis Ag Antibody drug conjugates having linkers comprising hydrophilic groups
US20220251141A1 (en) 2019-05-21 2022-08-11 Bristol-Myers Squibb Company Immunomodulators
CA3143087A1 (en) 2019-07-03 2021-01-07 Arnima BISHT Antibodies and methods of use
WO2021005599A1 (en) 2019-07-11 2021-01-14 Kahr Medical Ltd. Heterodimers and methods of use thereof
CN114174536A (en) 2019-07-15 2022-03-11 百时美施贵宝公司 anti-TREM-1 antibodies and uses thereof
CN114144435A (en) 2019-07-15 2022-03-04 百时美施贵宝公司 Antibodies against human TREM-1 and uses thereof
KR20220088868A (en) 2019-10-30 2022-06-28 브리스톨-마이어스 스큅 컴퍼니 immunomodulators
KR20220100950A (en) 2019-11-19 2022-07-18 브리스톨-마이어스 스큅 컴퍼니 Macrocyclic Peptides as PD-L1 Inhibitors and Immunomodulators for the Treatment of Cancer and Infectious Diseases
US20230063238A1 (en) 2020-01-06 2023-03-02 Bristol-Myers Squibb Company Immunomodulators
WO2021141684A1 (en) 2020-01-06 2021-07-15 Bristol-Myers Squibb Company Immunomodulators
AU2021228061A1 (en) 2020-02-27 2022-10-13 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Antibodies binding IL4R and uses thereof
JP2023515633A (en) 2020-02-28 2023-04-13 ブリストル－マイヤーズ スクイブ カンパニー Radiolabeled fibronectin-based scaffolds and antibodies and their theranostic uses
US20230140384A1 (en) 2020-03-09 2023-05-04 Bristol-Myers Squibb Company Antibodies to cd40 with enhanced agonist activity
JP2023517736A (en) 2020-03-16 2023-04-26 ブリストル－マイヤーズ スクイブ カンパニー Immunomodulator
EP4126902B1 (en) 2020-03-30 2023-12-06 Bristol-Myers Squibb Company Immunomodulators
CA3170570A1 (en) 2020-04-01 2021-10-07 James J. KOBIE Monoclonal antibodies against the hemagglutinin (ha) and neuraminidase (na) of influenza h3n2 viruses
EP4132971A1 (en) 2020-04-09 2023-02-15 Merck Sharp & Dohme LLC Affinity matured anti-lap antibodies and uses thereof
EP3901151A1 (en) 2020-04-21 2021-10-27 iOmx Therapeutics AG Halogenated-heteroaryl and other heterocyclic kinase inhibitors, and uses thereof
WO2021219731A2 (en) 2020-04-28 2021-11-04 Iomx Therapeutics Ag Bicyclic kinase inhibitors and uses thereof
WO2021222935A2 (en) 2020-04-28 2021-11-04 The Rockefeller University Neutralizing anti-sars-cov-2 antibodies and methods of use thereof
US20230181756A1 (en) 2020-04-30 2023-06-15 Novartis Ag Ccr7 antibody drug conjugates for treating cancer
CN116096758A (en) 2020-05-01 2023-05-09 诺华股份有限公司 Engineered immunoglobulins
US20230167193A1 (en) 2020-05-01 2023-06-01 Novartis Ag Immunoglobulin variants
WO2021226460A1 (en) 2020-05-08 2021-11-11 Bristol-Myers Squibb Company Immunomodulators
US20230192867A1 (en) 2020-05-15 2023-06-22 Bristol-Myers Squibb Company Antibodies to garp
US20230277524A1 (en) 2020-05-22 2023-09-07 Trailhead Biosystems Inc. Combination therapy for treatment of viral infections
CN116419747A (en) 2020-08-07 2023-07-11 福蒂斯治疗公司 CD46 targeting immunoconjugates and methods of use thereof
CA3191819A1 (en) 2020-09-09 2022-03-17 Hazel Szeto Methods and compositions for delivery of biotin to mitochondria
CN116322735A (en) 2020-10-02 2023-06-23 百时美施贵宝公司 Macrocyclic peptide borate immunomodulators
JP2023546020A (en) 2020-10-08 2023-11-01 ブリストル－マイヤーズ スクイブ カンパニー Novel dimeric immunomodulator
WO2022076796A1 (en) 2020-10-09 2022-04-14 Bristol-Myers Squibb Company Macrocyclic immunomodulators
JP2023548878A (en) 2020-11-04 2023-11-21 ザ ロックフェラー ユニバーシティー Neutralizing anti-SARS-COV-2 antibody
WO2022097061A1 (en) 2020-11-06 2022-05-12 Novartis Ag Anti-cd19 agent and b cell targeting agent combination therapy for treating b cell malignancies
EP4240765A2 (en) 2020-11-06 2023-09-13 Novartis AG Antibody fc variants
US20240025993A1 (en) 2020-11-06 2024-01-25 Novartis Ag Cd19 binding molecules and uses thereof
KR20230107281A (en) 2020-11-11 2023-07-14 비온테크 에스이 Monoclonal Antibodies to Programmed Death-1 Protein and Uses in Medicine
CN114685669A (en) 2020-12-30 2022-07-01 和铂医药(苏州)有限公司 Antibodies that bind TROP2 and uses thereof
WO2022155324A1 (en) 2021-01-15 2022-07-21 The Rockefeller University Neutralizing anti-sars-cov-2 antibodies
CN117157306A (en) 2021-03-24 2023-12-01 百时美施贵宝公司 Immunomodulators
EP4320159A1 (en) 2021-04-09 2024-02-14 Celldex Therapeutics, Inc. Antibodies against ilt4, bispecific anti-ilt4/pd-l1 antibody and uses thereof
EP4323380A2 (en) 2021-04-12 2024-02-21 Bristol-Myers Squibb Company Cyclic peptide immunomodulators
WO2022221720A1 (en) 2021-04-16 2022-10-20 Novartis Ag Antibody drug conjugates and methods for making thereof
WO2022226291A1 (en) 2021-04-22 2022-10-27 Dana-Farber Cancer Institute, Inc. Compositions and methods for treating cancer
EP4334343A2 (en) 2021-05-06 2024-03-13 The Rockefeller University Neutralizing anti-sars- cov-2 antibodies and methods of use thereof
KR20240013732A (en) 2021-05-26 2024-01-30 옥스포드 바이오테라퓨틱스 리미티드 Pharmaceutical combination comprising an anti-CD205 antibody and an immune checkpoint inhibitor
EP4351553A1 (en) 2021-06-09 2024-04-17 Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt GmbH Novel anti-fibrotic drugs
CN117425666A (en) 2021-06-09 2024-01-19 百时美施贵宝公司 Cyclic peptide immunomodulators
WO2023288213A1 (en) 2021-07-12 2023-01-19 Bristol-Myers Squibb Company Macrocyclic immunomodulators
KR20240035843A (en) 2021-07-19 2024-03-18 브리스톨-마이어스 스큅 컴퍼니 Macrocyclic immunomodulators
CN113773401B (en) 2021-09-15 2023-06-20 宜明昂科生物医药技术（上海）股份有限公司 Recombinant fusion protein targeting CD47 and PD-L1 and preparation and application thereof
CN113956363B (en) 2021-10-13 2023-03-31 宜明昂科生物医药技术（上海）股份有限公司 Recombinant fusion protein targeting CD47 and CD24 and preparation and application thereof
WO2023069994A1 (en) 2021-10-20 2023-04-27 Bristol-Myers Squibb Company Immunomodulators
WO2023073599A1 (en) 2021-10-28 2023-05-04 Novartis Ag Engineered fc variants
WO2023077521A1 (en) 2021-11-08 2023-05-11 Celldex Therapeutics, Inc Anti-ilt4 and anti-pd-1 bispecific constructs
WO2023089314A1 (en) 2021-11-18 2023-05-25 Oxford Biotherapeutics Limited Pharmaceutical combinations
WO2023102507A1 (en) 2021-12-03 2023-06-08 Bristol-Myers Squibb Company Macrocyclic immunomodulators
WO2023147399A1 (en) 2022-01-27 2023-08-03 The Rockefeller University Broadly neutralizing anti-sars-cov-2 antibodies targeting the n-terminal domain of the spike protein and methods of use thereof
WO2023192873A1 (en) 2022-03-28 2023-10-05 Bristol-Myers Squibb Company Macrocyclic immunomodulators
EP4257132A1 (en) 2022-04-08 2023-10-11 iOmx Therapeutics AG Sik3 inhibitors for treating diseases resistant to death receptor signalling
EP4257609A1 (en) 2022-04-08 2023-10-11 iOmx Therapeutics AG Combination therapies based on pd-1 inhibitors and sik3 inhibitors
TW202400658A (en) 2022-04-26 2024-01-01 瑞士商諾華公司 Multispecific antibodies targeting il-13 and il-18
US11932693B2 (en) 2022-05-12 2024-03-19 BioNTech SE Monoclonal antibodies directed against programmed death-1 protein and their use in medicine
WO2023225661A1 (en) 2022-05-20 2023-11-23 Bristol-Myers Squibb Company Macrocyclic immunomodulators
WO2024059472A1 (en) 2022-09-12 2024-03-21 Bristol-Myers Squibb Company Macrocyclic immunomodulators
WO2024062074A1 (en) 2022-09-21 2024-03-28 Sanofi Biotechnology Humanized anti-il-1r3 antibody and methods of use

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4136159A (en) * 1977-02-28 1979-01-23 New England Nuclear Corporation Radioassay of folates
JPS57186492A (en) * 1981-04-17 1982-11-16 Kyowa Hakko Kogyo Co Ltd Transformation of bacterium
NZ217821A (en) * 1985-10-10 1989-07-27 Biotech Australia Pty Ltd Oral delivery system; complex of active agent and vitamin b12 or analogue thereof
EP0273085A1 (en) * 1986-12-29 1988-07-06 IntraCel Corporation A method for internalizing nucleic acids into eukaryotic cells
US5135736A (en) * 1988-08-15 1992-08-04 Neorx Corporation Covalently-linked complexes and methods for enhanced cytotoxicity and imaging
US5108921A (en) * 1989-04-03 1992-04-28 Purdue Research Foundation Method for enhanced transmembrane transport of exogenous molecules

Also Published As

Publication number Publication date
US5635382A (en) 1997-06-03
ATE160583T1 (en) 1997-12-15
WO1990012096A1 (en) 1990-10-18
EP0466816A1 (en) 1992-01-22
US5820847A (en) 1998-10-13
AU5437590A (en) 1990-11-05
PT93646A (en) 1990-11-20
JPH05502787A (en) 1993-05-20
CA2013582A1 (en) 1990-10-03
JP3232347B2 (en) 2001-11-26
IE901201A1 (en) 1991-10-09
IE81171B1 (en) 2000-05-31
DE69031763D1 (en) 1998-01-08
CA2013580A1 (en) 1990-10-03
EP0466816A4 (en) 1992-05-20
IL93983A (en) 1997-02-18
US5108921A (en) 1992-04-28
IL93983A0 (en) 1991-01-31
DK0466816T3 (en) 1998-08-10
US5416016A (en) 1995-05-16
EP0466816B1 (en) 1997-11-26
ES2113346T3 (en) 1998-05-01
DE69031763T2 (en) 1998-06-25

Similar Documents

Publication Publication Date Title
CA2013582C (en) Method for enhancing transmembrane transport of exogenous molecules
US5688488A (en) Composition and method for tumor imaging
JP3814294B2 (en) Methods and compositions for lipidation of hydrophilic molecules
US6586524B2 (en) Cellular targeting poly(ethylene glycol)-grafted polymeric gene carrier
RU2113485C1 (en) Agent for transferring nucleic acids or their derivatives in human cells
US20030119724A1 (en) Ligands to enhance cellular uptake of biomolecules
US6372720B1 (en) Liposome fusion and delivery vehicle
US20210069232A1 (en) Click-modified mrna
JP2001515051A (en) Lipid-polyamide conjugates and compositions for nucleic acid delivery
US20100310468A1 (en) Recombinant albumins fused with poly-cysteine peptide and the methods for preparing the same
US6974698B1 (en) Methods for delivering biologically active molecules into cells
Hangeland et al. Tissue Distribution and Metabolism of the [32P]-Labeled Oligodeoxynucleoside Methylphosphonate-Neoglycopeptide Conjugate,[YEE (ah-GalNAc) 3]-SMCC-AET-pUmp T 7, in the Mouse
MXPA01012802A (en) Copolymers for the transfer of nucleic acids to the cell.
US20020058615A1 (en) Endothelial specific targeting
WO1990012095A1 (en) Method for enhancing transmembrane transport of exogenous molecules
EP1541135A1 (en) Hollow nanoparticle having modified cysteine residue and drug with the use thereof
AU749113B2 (en) Compositions and methods for highly efficient transfection
JPWO2005054486A1 (en) Gene transfer reagent preparation method
EP0725141A1 (en) Method of controlled genetic transformation of an animal mammary gland and a device for introducing genetic material into the mammary duct of an animal mammary gland
Pipkorn et al. Synthesis and application of functional peptides as cell nucleus‐directed molecules in the treatment of malignant diseases
US20030100496A1 (en) Compositions and methods for highly efficient transfection

Legal Events

Date Code Title Description
EEER Examination request
MKLA Lapsed
MKEC Expiry (correction)

Effective date: 20121202