Autoimmune Disease patents
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| Anti-kir antibodies|
Provided herein are compositions (e.g., killer cell immunoglobulin-like receptor (kir)-targeting agents) that target a subset of t lymphocytes present in disease states (e.g., lupus and other autoimmune diseases) and methods of treating conditions and/or diseases therewith. In particular, anti-kir antibodies, fragments thereof, or related compositions are provided for the treatment of conditions and/or diseases (e.g., lupus and other autoimmune diseases, atherosclerosis, etc.)..
The Regents Of The University Of Michigan
| Pro-drugs of nsaias with very high skin and membranes penetration rates and their new medicinal uses|
The novel positively charged pro-drugs of nsaias in the general formulas (1, 2a, 2b, 2c, or 2d) “structure 1, 2a, 2b, 2c, or 2d” were designed and synthesized. The compounds of the general formulas (1, 2a, 2b, 2c, or 2d) “structure 1, 2a, 2b, 2c, or 2d” indicated above can be prepared from metal salts, organic base salts, or immobilized base salts of nsaias with suitable halide compounds.
Techfields Pharma Co., Ltd.
| Compositions and methods for the prevention and treatment of autoimmune conditions|
The methods include selectively reducing or expanding t cells according to the antigenic specificity of the t cells. Therefore, the present invention can be used to reduce or eliminate pathogenic t cells that recognize autoantigens, such as beta cell specific t cells.
Uti Limited Partnership
| Methods of treating allergies and autoimmune diseases with homogenate of axenic c. elegans|
Methods of using axenic c. Elegans homogenate for treating allergies or an autoimmune disease are disclosed.
The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc.
| Modulators of syndecan-2 and uses thereof|
Modulators of syndecan-2, such as an antibody to syndecan-2 that cross-links syndecan-2 on the cell surface or a syndiecan-2 polypeptide that interferes with syndecan-2 receptor binding, is used to regulate a th17 mediated disease such as an autoimmune disease, fibrosis or cancer.. .
Orbsen Therapeutics Limited
| Il-17 production inhibitory composition|
Provided is a composition for preventing or treating il-17-related diseases, more specifically, autoimmune diseases and inflammatory diseases induced by an increase of il-17. The il-17 production inhibitory composition is characterized by containing mesenchymal stem cells originated from an adipose tissue as an active ingredient.
Anterogen Co., Ltd.
| Polyethylene glycol-cactus oligopeptide bonding rapamycin derivatives|
The present invention provides compounds represented by formula (i) and pharmaceutical acceptable salts thereof, preparation method therefor and pharmaceutical composition containing the compounds represented by formula (i) and pharmaceutical acceptable salts thereof. In the compounds of the present invention, each terminal group of polyethylene glycol molecule can bond with a plurality of rapamycin molecules by cactus oligopeptide, with the loading rate of the pharmaceutical being increased.
Jenkem Technology Co., Ltd.
|Biological markers and methods for predicting response to b-cell antagonists|
Biological markers that predict patient responsiveness to b-cell antagonists are provided. Also provided are methods of using such biological markers.
|Methods of reducing serum levels of fc-containing agents using fcrn antagonists|
Provided are novel methods of reducing the serum levels of fc-containing agents (e.g., antibodies and immunoadhesins) in a subject. These methods generally comprise administering to the subject an effective amount of an isolated fcrn-antagonist that binds specifically to fcrn with increased affinity and reduced ph dependence relative to the native fc region.
|Il-3 blockade in systemic lupus erythematosus and multiple sclerosis|
The present invention relates to anti-il-3 antibodies or il-3 binding fragments thereof for use in the treatment of an autoimmune disease selected from the group consisting of systemic lupus erythematosus and multiple sclerosis, and to pharmaceutical compositions comprising such an antibody or antibody fragment.. .
Novel scorpion toxin analogue and treating autoimmune diseases
A novel peptide analogue of the heterometrus spinnifer toxin hstx1 is disclosed along with its application as, for example, a therapeutic agent for treating an autoimmune disease such as multiple sclerosis (ms) or rheumatoid arthritis (ra). The analogue comprises a peptide with an amino acid substitution at amino acid position 14 of the wild-type (wt) peptide sequence (or a position corresponding to position 14 of the wt peptide sequence).
Baylor College Of Medicine
Polycyclic inhibitors of cyclin-dependent kinase 7 (cdk7)
The present invention provides novel compounds of formula (i), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the inventive compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g., leukemia, lymphoma, melanoma, multiple myeloma, breast cancer, ewing's sarcoma, osteosarcoma, brain cancer, neuroblastoma, lung cancer), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject.
Dana-farber Cancer Institute, Inc.
Heteromaromatic compounds useful for the treatment of prolferative diseases
The present invention provides novel compounds of formula (i) and formula (ii), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g., leukemia, melanoma, multiple myeloma), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject.
Syros Pharmaceuticals, Inc.
Heteroaromatic compounds useful for the treatment of prolferative diseases
The present invention provides novel compounds of formula (i), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g., leukemia, melanoma, multiple myeloma), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject.
Dana-farber Cancer Institute, Inc.
Cell, tissue and organ protection using a magnetic field
Methods and apparatus are provided for applying low magnetic fields (<400 g) to mammalian cells, tissues and organs for protection from the damaging effects of ionizing radiation and other oxygen dependent injuries that involve the radical pair mechanism. The magnetic fields are generated by fixed magnets or active magnets and used to enhance the survival of healthy cells during radiation treatment for cancer, to protect workers from radiation within nuclear power plants, to protect astronauts from radiation during long space voyages, to increase working time in exposed environments, to provide a safe room in hazardous locations, and to protect normal tissue during radiation treatment and in medical imaging modalities that use ionizing radiation (x-ray, ct, mammography).
The Trustees Of The University Of Pennsylvania
Securinine and norsecurinine analogue compounds for the treatment of myeloid disorders
The present application relates to securinine or norsecurinine analogues that, when administered to immature myeloid cells, promote differentiation of these cells to mature cells that do not readily proliferate. Therefore, the agents are useful in the treatment of myeloid disorders including myeloproliferative disorders, acute myeloid leukemia, and autoimmune diseases.
Case Western Reserve University
Her2/neu-specific antibodies and methods of using same
This invention relates to antibodies that specifically bind her2/neu, and particularly chimeric 4d5 antibodies to her2/neu, which have reduced glycosylation as compared to known 4d5 antibodies. The invention also relates to methods of using the 4d5 antibodies and compositions comprising them in the diagnosis, prognosis and therapy of diseases such as cancer, autoimmune diseases, inflammatory disorders, and infectious disease..
Purinone derivatives as tyrosine kinase inhibitors
The present disclosure provides compounds and pharmaceutically acceptable salts thereof that are tyrosine kinase inhibitors, in particular blk, bmx, egfr, her2, her4, itk, tec, btk, and txk and are therefore useful for the treatment of diseases treatable by inhibition of tyrosine kinases such as autoimmune diseases, cancer and inflammatory diseases. Also provided are pharmaceutical compositions containing such compounds and pharmaceutically acceptable salts thereof and processes for preparing such compounds and pharmaceutically acceptable salts thereof..
Principia Biopharma Inc.
Thiadiazolidinediones as gsk-3 inhibitors
The present invention relates to new thiadiazolidinediones of formula (i), or any pharmaceutically acceptable salt, solvate or prodrug thereof, and its use in the treatment of a disease in which glycogen synthase kinase 3 (gsk-3) is involved, particularly neurodegenerative diseases, inflammatory and autoimmune diseases and cardiovascular disorders. Additionally, there is provided a process for preparing such compounds, as well as pharmaceutical compositions comprising them..
Asd Therapeutics Partners Llc
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Benzazepine dicarboxamide compounds
Wherein r1 to r4 are as defined in the description and in the claims, as well as pharmaceutically acceptable salts thereof. These compounds are tlr agonists and may therefore be useful as medicaments for the treatment of diseases such as cancer, autoimmune diseases, inflammation, sepsis, allergy, asthma, graft rejection, graft-versus-host disease, immunodeficiencies, and infectious diseases..
Phosphorylcholine conjugates and uses thereof
The present invention provides phosphorylcholine conjugates and pharmaceutical compositions comprising same for the prevention or treatment of autoimmune diseases. In particular, the conjugates of the present invention are effective in treating autoimmune diseases associated with pathological inflammation..
Pharmaceutical formulations of a bruton's tyrosine kinase inhibitor
Described herein are pharmaceutical formulations of bruton's tyrosine kinase (btk) inhibitor 1-((r)-3-(4-amino-3-(4-phenoxyphenyl)-1h-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one. Also disclosed are methods of using the btk inhibitor, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions..
Diagnosis and treatment of autoimmune diseases
Methods, kits and compositions for diagnosing and treating autoimmune diseases such as rheumatiodi arthritis, crohn's disease, and ulcerative colitis.. .
Monitoring health and disease status using clonotype profiles
There is a need for improved methods for determining the diagnosis and prognosis of patients with conditions, including autoimmune disease and cancer, especially lymphoid neoplasms, such as lymphomas and leukemias. Provided herein are methods for using dna sequencing to identify personalized, or patient-specific biomarkers in patients with lymphoid neoplasms, autoimmune disease and other conditions.
Adaptive Biotechnologies Corp.
Therapeutic use of anti-cd22 antibodies for inducing trogocytosis
Disclosed are methods and compositions of anti-b cell antibodies, preferably anti-cd22 antibodies, for diagnosis, prognosis and therapy of b-cell associated diseases, such as b-cell malignancies, autoimmune disease and immune dysfunction disease. Preferably, the antibodies induce trogocytosis of b-cell antigens, such as cd19, cd20, cd21, cd22, cd79b, cd44, cd62l, or β7-integrin.
Novel receptor trem (triggering receptor expressed on myeloid cells) and uses thereof
Novel activating receptors of the lg super-family expressed on human myeloid cells, called trem(s) (triggering receptor expressed on myeloid cells) are provided. Specifically, two (2) members of trems, trem-1 and trem-2 are disclosed.
Novo Nordisk A/s
Chromene derivatives as inhibitors of tcr-nck interaction
And which present the ability to inhibit the lymphocytes proliferation mediated by the tcr interaction with nck, so that the present invention also relates to the use of these compounds for the treatment of diseases or conditions wherein said interaction triggers a complication such as transplant rejection reactions, immune or autoimmune diseases, inflammatory diseases or proliferative diseases.. .
Carboxylic acid compounds
The present disclosure concerns at least one entity chosen from compounds of formula (i) and pharmaceutically acceptable salts thereof: (i) wherein the variable groups x, r1, r2, r3 m, n and p are as defined herein. The present disclosure also relates to methods for the preparation of at least one such entity, and intermediates useful in the preparation thereof, to pharmaceutical compositions containing at least one such entity, to the use of at least one such entity in the preparation of medicaments, and to the use of at least one such entity in the treatment of conditions such as, for example, allergic diseases, autoimmune diseases, viral diseases, and cancer..
And/or a salt thereof; wherein r is —oh or —op(o)(oh)2. Also disclosed are methods of using such compounds as selective agonists for g protein-coupled receptor s1p1, and pharmaceutical compositions comprising such compounds.
Nucleic acids comprising formula (nuglxmgnnv)a and derivatives thereof as immunostimulating agent/adjuvant
The present invention relates to nucleic acids of the general formula (i): (nuglxmgnnv)a and derivatives thereof as an immunostimulating agent/adjuvant and to compositions containing same, optionally comprising an additional adjuvant. The present invention furthermore relates to a pharmaceutical composition or to a vaccine, each containing nucleic acids of formula (i) above and/or derivatives thereof as an immunostimulating agent, and optionally at least one additional pharmaceutically active component, e.g.
Methods for induction of antigen-specific regulatory t cells
The present invention relates to methods of obtaining antigen-specific regulatory cells in vitro or in vivo. The regulatory cells are obtainable by inducing apoptosis of antigen-presenting cells by nkt cells.
Treating organ-specific t cell mediated autoimmune diseases
The specification provides methods of treating a subject with an organ-specific t cell mediated autoimmune disease.. .
University Of Massachusetts
Methods of identifying subjects responsive to treatment for an autoimmune disease and compositions for treating the same
Methods of identifying a subject having an autoimmune disease, such as type 1 diabetes, as likely to respond to treatment with a tumor necrosis factor-alpha (tnf-α) receptor ii activator, involving measuring cd8 protein density on the surface of autoreactive cd8+ t cells and identifying the subject as likely to respond to the treatment if the cd8 protein density is reduced relative to a reference cd8+ t cell. For type 1 diabetes, the method may involve measuring c-peptide levels in an in vitro biological sample from the subject, identifying the subject as likely to respond to the treatment if the c-peptide levels are detectable, and identifying the subject as unlikely to respond to the treatment if the c-peptide levels are substantially undetectable.
The General Hospital Corporation
Antibody therapeutics that bind cd137
There is disclosed compositions and methods relating to or derived from anti-cd137 antibodies. More specifically, there is disclosed fully human antibodies that bind cd137, cd137-antibody binding fragments and derivatives of such antibodies, and cd137-binding polypeptides comprising such fragments.
Sorrento Therapeutics, Inc.
T cell activation inhibitor, pharmaceutical composition containing same, and screening t cell activation inhibiting substance
Provided is a t cell activation inhibitor containing an rgm inhibiting substance such as an anti-rgm neutralizing antibody and the like as an active ingredient. The t cell activation inhibitor is useful as a pharmaceutical composition for the prophylaxis or treatment of autoimmune diseases such as multiple sclerosis and the like, and other diseases caused by t cell activation.
Mitsubishi Tanabe Pharma Corporation
Superkines and synthekines: repurposed cytokines with new and enhanced signaling activities
Disclosed herein are il-4 cytokine compositions with enhanced biological activity having increased selectivity for il-4 cytokine receptors, and methods for their use. These compositions encompass interleukin-4 (il-4) muteins.
Novel compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders
Wherein r1a, r1b, r2, r4, r5, r6a, r6b, r7, r8, w, x, cy, and the subscript a are as defined herein. The present invention relates to compounds inhibiting autotaxin (npp2 or enpp2), methods for their production, pharmaceutical compositions comprising the same, and methods of treatment using the same, for the prophylaxis and/or treatment of diseases involving fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders, and/or abnormal angiogenesis associated diseases by administering the compound of the invention..
Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders.
The present invention relates to novel compounds according to formula i that antagonize gpr84, a g-protein-coupled receptor that is involved in inflammatory conditions, and methods for the production of these novel compounds, pharmaceutical compositions comprising these compounds, and methods for the prevention and/or treatment of inflammatory conditions (for example inflammatory bowel diseases (ibd), rheumatoid arthritis, vasculitis, lung diseases (e.g. Chronic obstructive pulmonary disease (copd) and lung interstitial diseases (e.g.
Fused heterocyclic compound, preparation method therefor, pharmaceutcial composition, and uses thereof
Disclosed are a fused heterocyclic compound, a preparation method therefor, a pharmaceutical composition, and uses thereof. The fused heterocyclic compound is shown in formula i, formula ii, or formula iii.
Shanghai Yingli Pharmaceutical Co., Ltd.
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New pi3k/akt/mtor inhibitors and pharmaceutical uses thereof
The invention relates to new pi3k/akt/m tor inhibitors and their use for the prevention and/or the treatment of a disease selected from the group consisting of: inflammatory diseases, autoimmune diseases, neurodegenerative diseases, cancers, transplant rejection, diseases characterized by a premature aging and tuberous sclerosis.. .
Institut National De La Sante Et De La Recherche Medicale (inserm)
Chromene derivatives substituted by alkoxide as inhibitors of the tcr-nck interaction
And that present the capacity to inhibit the proliferation of lymphocytes mediated by the nck interaction with tcr, so that the present invention also relates to the use of these compounds for the treatment of diseases or conditions where said interaction triggers a complication such as transplant rejection reactions, immune or autoimmune diseases, inflammatory diseases or proliferative diseases.. .
Glycotargeting therapeutics are useful in the treatment of transplant rejection, autoimmune disease, food allergy, and immune response against a therapeutic agent.. .
Ecole Polytechnique Federale De Lausanne (epfl)
Combination therapy with anti-cd74 and anti-cd20 antibodies provides enhanced toxicity to b-cell diseases
Disclosed are compositions and methods comprising combinations of anti-cd74 and anti-cd20 antibodies or antigen-binding fragments thereof. The antibody combination may also be used with a therapeutic agent that is attached to antibody or fragment thereof or separately administered.
Ibc Pharmaceuticals, Inc.
Probiotic enhancement of steroid and immune suppressor activity in mammals with chronic diseases
This invention relates to use of probiotics, particularly p acidilactici and s boulardii, for use in conjunction with steroids and other immune suppressor agents to ameliorate symptoms of autoimmune diseases, especially disease symptoms arising from the body's production of antibodies against autologous blood cells. The practice of the invention sustains ameliorative response associated with immune suppressor agents while lowering the amount of immune suppressor agents required for treatment..
Imagilin Technology, Llc
Methods for treating and preventing multiple sclerosis
We have discovered that lrg-47 (also called p47 gtpase), plays a central role in the pathogenesis of multiple sclerosis, and that inhibition of lrg-47 activity by anti-lrg-47 antibodies or of lrg-47 expression by sirna dramatically reduce the pathology and symptoms of multiple sclerosis. Certain embodiments of the invention are directed to the therapeutic use of anti-lrg-47 antibodies (mouse or rabbit or other antibodies that are humanized or human antibodies to lrg-47, preferably antibodies made against human lrg-47) or sirna or antisense nucleotides that specifically hybridize with the gene or mrna or cdna encoding human lrg-47 to treat or prevent multiple sclerosis and other autoimmune diseases that are t-cell-mediated.
The Trustees Of Columbia University In The City Of New York
Antibody therapeutics that bind ctla4
There is disclosed compositions and methods relating to or derived from anti-ctla4 antibodies. More specifically, there is disclosed fully human antibodies that bind ctla4, ctla4-antibody binding fragments and derivatives of such antibodies, and ctla4-binding polypeptides comprising such fragments.
Sorrento Therapeutics, Inc.
Substituted nicotinimide inhibitors of btk and their preparation and use in the treatment of cancer, inflammation and autoimmune disease
And pharmaceutically acceptable salts, syntheses, intermediates, formulations, and methods of treating diseases including cancer, inflammation, and autoimmune disease mediated at least in part by bruton's tyrosine kinase (btk).. .
Compositions and methods to image and quantify inflammation
Compositions and methods for assessing inflammation in a subject. The preset disclosure provides compositions for labeling leukocytes with a 19f-containing perfluoropolyether molecule ex vivo.
Amorphous magnesium-substituted calcium phosphate compositions and their uses
Amorphous magnesium-substituted calcium, phosphate compositions and their medical uses are described, in particular for use in delivering cargo materials, such as cargo molecules or cargo nanoparticles contained in pores of the amorphous magnesium-substituted calcium phosphate to cells of the immune system, for example as therapeutic approaches for the treatment of inflammatory bowel diseases, and in particular crohn's disease, autoimmune diseases, allergy and for therapeutic vaccination.. .
Medical Research Council
Engineered cxcl12 alpha locked dimer polypeptide
The present invention provides a novel cxcl12-α2 locked dimer polypeptide, pharmaceutical compositions thereof, and methods of using said dimer in the treatment of cancer, inflammatory disorders, autoimmune disease, and hiv/aids.. .
The Rockefeller University
Cyclic peptide conjugates and methods of use
The present invention concerns cyclic compounds, compositions comprising the cyclic compounds, linkers, a method of preparing a carrying agent:cyclic compound adduct, a method for treating disorders such as proliferation disorders (e.g., malignancies), bone deficiency diseases, and autoimmune diseases, and a method for suppressing the growth of, or inducing apoptosis in, cells (e.g., malignant cells).. .
Novel fused pyrimidine derivatives for inhibition of tyrosine kinase activity
A novel fused pyrimidine derivative has an inhibitory activity for tyrosine kinases. A pharmaceutical composition for preventing or treating cancers, tumors, inflammatory diseases, autoimmune diseases, or immunologically mediated diseases contains the fused pyrimidine derivative as an active ingredient..
Hanmi Science Co., Ltd
Bicyclic alkyne derivatives and uses thereof
The present invention relates to certain compounds (e.g., imidazopyrazine, imidazopyridine, imidazopyridazine and imidazpyrimidine compounds) that act as inhibitors of the map kinase interacting kinases mnk2a, mnk2b, mnk1a, and mnk1b. The present invention further relates to pharmaceutical compositions comprising these compounds, and to the use of the compounds for the prevention and treatment of diseases (e.g., proliferative diseases (e.g., cancer), inflammatory diseases, autoimmune diseases, metabolic diseases, and neurodegenerative diseases (e.g.
Agency For Science, Technology And Research
Aza-heteroaryl compounds as pi3k-gamma inhibitors
And pharmaceutically acceptable salts thereof, wherein x, y, z, a, w, r4, r5, and r6 are defined herein, that inhibit the activity of phosphoinositide 3-kinases-gamma (pi3kγ) and are useful in the treatment of diseases related to the activity of pi3kγ including, for example, autoimmune diseases, cancer, cardiovascular diseases, and neurodegenerative diseases.. .
Protein-cell conjugate, preparation method and use thereof
The present invention pertains to immunology, biomedicine field, specifically relates to a protein-cell conjugate, which is characterized in that the protein and the cell are coupled via a bifunctional cross-linking agent. The present invention further relates to a preparation method and uses of the protein-cell conjugate.
Cansbio (beijing) Biotechnology Co., Ltd.
Nitrogen-containing bicyclic aromatic heterocyclic compound
On the basis of a cathepsin s inhibitory effect, an excellent agent for treating or preventing autoimmune disease, allergic disease, graft rejection of an organ, bone marrow or tissue, systemic lupus erythematosus, or the like is provided. It was found that a nitrogen-containing bicyclic heterocyclic compound has an excellent cathepsin s inhibitory effect, thereby completing the invention.
Astellas Pharma Inc.
Treatment of diseases caused by abnormal lymphocyte function with an hdac6 inhibitor
An hdac6 inhibitor (a compound of formula i) is shown to reduce the pathogenesis associated with the b cell mediated autoimmune disease, systemic lupus erythematosus (sle) administration of a compound of formula i attenuated many of the symptoms characteristic of sle including splenomegaly, abnormal b cell differentiation, an increase in the number double-negative thymic t cells, an increase in the level of auto-antibodies such as anti-dsdna, immune complex-mediated glomerulonephritis and an increase in inflammatory cytokine production. Treatment with a compound of formula i also increased the number of the subject's splenic treg cells while removing circulating auto-antibodies inhibition of hdac6 altered bone marrow b cell differentiation by increasing the percentage of cells in the early-stage developmental fractions of both pro- and pre-b cells.
Virginia Tech Intellectual Properties, Inc.
Antibodies against pd-1 and uses thereof
The present invention provides antibodies and antigen-binding fragments that specifically bind pd-1 (programmed death 1), thereby modulating immune responses in general, and those mediated by tcr and cd28, in particular. The disclosed compositions and methods may be used for example, in treating autoimmune diseases, inflammatory disorders, allergies, transplant rejection, cancer and other immune system disorders..
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