COMPOSITIONS AND METHODS FOR TREATING INFLAMMATION AND AUTO-IMMUNE DISEASES

• US 20080160036A1
• Filed: 12/27/2007
• Published: 07/03/2008
• Est. Priority Date: 12/27/2006
• Status: Active Grant

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Chen, Lieping
• Granted Patent: US 7,931,896 B2
• Time in Patent Office: Days
• US Class Current: 424/179.1
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61M 1/3413 Diafiltration
• CPC Class Codes: A61M 1/3679 by absorption A61M1/3675 takes precedence
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 33/02 : Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 14/70532 : B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 2319/30 : Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: G01N 2800/102 : Arthritis; Rheumatoid arthritis, i.e. inflammation of peripheral joints
• CPC Class Codes: G01N 2800/104 : Lupus erythematosus [SLE]
• CPC Class Codes: G01N 2800/24 : Immunology or allergic disorders SLE G01N2800/104
• CPC Class Codes: G01N 2800/52 : Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Compositions containing soluble B7-H4 (sH4) antagonists in an amount effective to reduce, inhibit, or mitigate an inflammatory response in an individual and methods for the treatment or prophylaxis of inflammatory disorders and autoimmune diseases or disorders are provided. Soluble H4 has been discovered to interfere with B7-H4 activity including B7-H4'"'"'s activity as an inhibitor of T cell immunity. Thus, interference of sH4 biological activity is an effective method to restore B7-H4 activity and thereby provide an effective method for treating inflammatory diseases or disorders including autoimmune diseases or disorders.

Claims

1. A pharmaceutical composition dosage unit comprising a soluble B7-H4 antagonist in an amount effective to reduce or inhibit one or more symptoms of an inflammatory response in an individual in need thereof, and a pharmaceutically acceptable carrier for administration of the antagonist.

2. The pharmaceutical composition of claim 1, wherein the B7-H4 antagonist is a fusion protein comprising a first fusion partner including all or a part of a B7-H4 extracellular domain fused (i) directly to a second polypeptide or, (ii) optionally, fused to a linker peptide sequence that is fused to the second polypeptide.

3. The pharmaceutical composition of claim 2 wherein the first fusion partner comprises the membrane distal IgV domain and the membrane proximal IgC domain of B7-H4.

4. The pharmaceutical composition of claim 1 in a kit comprising the antagonist in a first unit and the pharmaceutically acceptable carrier in a second unit, wherein the units are combined for administration.

5. The pharmaceutical composition of claim 1 wherein the inflammatory response is associated with an autoimmune disease or disorder.

6. The pharmaceutical composition of claim 1 wherein the inflammatory response is neutrophil-mediated.

7. The pharmaceutical composition of claim 5 wherein the autoimmune disease or disorder is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, alopecia greata, anklosing spondylitis, antiphospholipid syndrome, autoimmune Addison'"'"'s disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome (ALPS), autoimmune thrombocytopenic purpura (ATP), Beheet'"'"'s disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue syndrome immune deficiency, syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, cicatricial pemphigoid, cold agglutinin disease, Crest syndrome, Crohn'"'"'s disease, Dego'"'"'s disease, dermatomyositis, dermatomyositis—

juvenile, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia—

fibromyositis, grave'"'"'s disease, guillain-barre, hashimoto'"'"'s thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), Iga nephropathy, insulin dependent diabetes (Type I), juvenile arthritis, Meniere'"'"'s disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglancular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud'"'"'s phenomenon, Reiter'"'"'s syndrome, rheumatic fever, sarcoidosis, scleroderma, Sjogren'"'"'s syndrome, stiff-man syndrome, Takayasu arteritis, temporal arteritis/giant cell arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, and Wegener'"'"'s granulomatosis.

8. A method for treating or inhibiting one or more symptoms of an inflammatory response in an individual in need thereof comprising

administering to the individual an antagonist of soluble B7-H4 in an amount effective to reduce or inhibit the one or more symptoms of the inflammatory response in the individual.

9. The method of claim 8 wherein the inflammatory response is associated with an autoimmune disease or disorder.

10. The method of claim 9 wherein the individual has an autoimmune disease selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, alopecia greata, anklosing spondylitis, antiphospholipid syndrome, autoimmune addison'"'"'s disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome (alps), autoimmune thrombocytopenic purpura (ATP), Behcet'"'"'s disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue syndrome immune deficiency, syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, cicatricial pemphigoid, cold agglutinin disease, Crest syndrome, Crohn'"'"'s disease, Dego'"'"'s disease, dermatomyositis, dermatomyositis—

juvenile, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia—

fibromyositis, grave'"'"'s disease, guillain-barre, hashimoto'"'"'s thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), Iga nephropathy, insulin dependent diabetes (Type I), juvenile arthritis, Meniere'"'"'s disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglancular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud'"'"'s phenomenon, Reiter'"'"'s syndrome, rheumatic fever, sarcoidosis, scleroderma, Sjogren'"'"'s syndrome, stiff-man syndrome, Takayasu arteritis, temporal arteritis/giant cell arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, and Wegener'"'"'s granulomatosis.

11. The method of claim 8 wherein the soluble B7-H4 antagonist comprises a B7-H4 polypeptide comprising at least 80% sequence identity to B7-H4 extracellular domain and is capable of suppressing or inhibiting humoral immunity, cellular immunity, or both.

12. The method of claim 11, wherein the soluble B7-H4 antagonist comprises an immunoglobin or fragment thereof.

13. The method of claim 12, wherein the immunoglobin or fragment thereof comprises an immunoglobin Fe region.

14. The method of claim 8 comprising expressing in the individual a nucleic acid encoding a B7-H4 polypeptide comprising at least 80% sequence identity to B7-H4 extracellular domain.

15. The method of claim 14 wherein the B7-H4 polypeptide further comprises an immunoglobin Fe region.

16. A method for assessing the severity or risk of developing an autoimmune disease or disorder comprising

obtaining a biological sample from an individual;

determining levels of soluble B7-H4 in the sample, and

comparing the levels of soluble B7-H4 in the sample to levels in a normal control or controls with levels known to be indicative of a severity or risk of developing an autoimmune disease or disorder.

17. The method of claim 16 wherein the autoimmune disease or disorder is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, alopecia greata, anklosing spondylitis, antiphospholipid syndrome, autoimmune addison'"'"'s disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome (alps), autoimmune thrombocytopenic purpura (ATP), Behcet'"'"'s disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue syndrome immune deficiency, syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, cicatricial pemphigoid, cold agglutinin disease, Crest syndrome, Crohn'"'"'s disease, Dego'"'"'s disease, dermatomyositis, dermatomyositis—

juvenile, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia—

fibromyositis, grave'"'"'s disease, guillain-barre, hashimoto'"'"'s thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), Iga nephropathy, insulin dependent diabetes (Type I), juvenile arthritis, Meniere'"'"'s disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglancular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud'"'"'s phenomenon, Reiter'"'"'s syndrome, rheumatic fever, sarcoidosis, scleroderma, Sjogren'"'"'s syndrome, stiff-man syndrome, Takayasu arteritis, temporal arteritis/giant cell arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, and Wegener'"'"'s granulomatosis.

18. A method for treating or inhibiting an inflammatory response comprising

a) removing biological fluid from an individual;

b) removing soluble B7-H4 from the biological fluid to produce treated biological fluid;

c) returning the treated biological fluid to the individual.

19. The method of claim 18, wherein the biological fluid comprises whole blood or plasma.

20. The method of claim 18, wherein removing soluble B7-H4 occurs by ultrafiltration, apheresis, or dialysis.

21. The method of claim 18, wherein soluble B7-H4 is selectively removed from the biological fluid using immunosorbent techniques.