Claims for Patent: 9,944,711

Summary for Patent: 9,944,711

Title:	Antibodies against human CD38
Abstract:	Isolated monoclonal antibodies which bind to human CD38 and related antibody-based compositions and molecules, are disclosed. Also disclosed are pharmaceutical compositions comprising the antibodies and therapeutic and diagnostic methods for using the antibodies.
Inventor(s):	De Weers; Michel (Houten, NL), Walseth; Tim (Roseville, MN), Van De Winkel; Jan (Zeist, NL), Vink; Tom (Alphen aan den Rijn, NL), Parren; Paul (Odijk, NL)
Assignee:	GENMAB A/S (Copenhagen V, DK)
Application Number:	14/990,869
Patent Claims:	1. A method of inhibiting growth and/or proliferation, or migration, or inducing phagocytosis of a cell expressing CD38, comprising contacting the cell with an antibody that binds to human CD38 (SEQ ID NO: 52), wherein the antibody comprises: (i) a VH CDR1 having the sequence as set forth in any one of SEQ ID NOs: 3, 8, 13, 18, and 23, a VH CDR2 having the sequence as set forth in any one of SEQ ID NOs: 4, 9, 14, 19, and 24, a VH CDR3 having the sequence as set forth in any one of SEQ ID NOs: 5, 10, 15, 20, and 25, a VL CDR1 having the sequence as set forth in any one of SEQ ID NOs: 28, 33, 38, 43, and 48, a VL CDR2 having the sequence as set forth in any one of SEQ ID NOs: 29, 34, 39, 44, and 49, and a VL CDR3 having the sequence as set forth in any one of SEQ ID NOs: 30, 35, 40, 45, and 50, (ii) a VH CDR1 having the sequence as set forth in SEQ ID NO: 3, a VH CDR2 having the sequence as set forth in SEQ ID NO: 4, a VH CDR3 having the sequence as set forth in SEQ ID NO: 5, a VL CDR1 having the sequence as set forth in SEQ ID NO: 28, a VL CDR2 having the sequence as set forth in SEQ ID NO: 29, and a VL CDR3 having the sequence as set forth in SEQ ID NO: 30, (iii) a VH CDR1 having the sequence as set forth in SEQ ID NO: 8, a VH CDR2 having the sequence as set forth in SEQ ID NO: 9, a VH CDR3 having the sequence as set forth in SEQ ID NO: 10, a VL CDR1 having the sequence as set forth in SEQ ID NO: 33, a VL CDR2 having the sequence as set forth in SEQ ID NO: 34, and a VL CDR3 having the sequence as set forth in SEQ ID NO: 35, (iv) a VH CDR1 having the sequence as set forth in SEQ ID NO: 13, a VH CDR2 having the sequence as set forth in SEQ ID NO: 14, a VH CDR3 having the sequence as set forth in SEQ ID NO: 15, a VL CDR1 having the sequence as set forth in SEQ ID NO: 38, a VL CDR2 having the sequence as set forth in SEQ ID NO: 39, and a VL CDR3 having the sequence as set forth in SEQ ID NO: 40, (v) a VH CDR1 having the sequence as set forth in SEQ ID NO: 18, a VH CDR2 having the sequence as set forth in SEQ ID NO: 19, a VH CDR3 having the sequence as set forth in SEQ ID NO: 20, a VL CDR1 having the sequence as set forth in SEQ ID NO: 43, a VL CDR2 having the sequence as set forth in SEQ ID NO: 44, and a VL CDR3 having the sequence as set forth in SEQ ID NO: 45, or (vi) a VH CDR1 having the sequence as set forth in SEQ ID NO: 23, a VH CDR2 having the sequence as set forth in SEQ ID NO: 24, a VH CDR3 having the sequence as set forth in SEQ ID NO: 25, a VL CDR1 having the sequence as set forth in SEQ ID NO 48, a VL CDR2 having the sequence as set forth in SEQ ID NO: 49, and a VL CDR3 having the sequence as set forth in SEQ ID NO: 50, an immunoconjugate comprising the antibody, or a bispecific antibody comprising the antibody, such that the growth and/or proliferation, or migration of the cell is inhibited, or phagocytosis of the cell is induced. 2. A method of treating a cancer, inflammatory disorder, immune disorder, or autoimmune disorder involving cells expressing CD38 comprising administering to a subject in need thereof an antibody that binds to human CD38 (SEQ ID NO: 52), wherein the antibody comprises: (i) a VH CDR1 having the sequence as set forth in any one of SEQ ID NOs: 3, 8, 13, 18, and 23, a VH CDR2 having the sequence as set forth in any one of SEQ ID NOs: 4, 9, 14, 19, and 24, a VH CDR3 having the sequence as set forth in any one of SEQ ID NOs: 5, 10, 15, 20, and 25, a VL CDR1 having the sequence as set forth in any one of SEQ ID NOs: 28, 33, 38, 43, and 48, a VL CDR2 having the sequence as set forth in any one of SEQ ID NOs: 29, 34, 39, 44, and 49, and a VL CDR3 having the sequence as set forth in any one of SEQ ID NOs: 30, 35, 40, 45, and 50, (ii) a VH CDR1 having the sequence as set forth in SEQ ID NO: 3, a VH CDR2 having the sequence as set forth in SEQ ID NO: 4, a VH CDR3 having the sequence as set forth in SEQ ID NO: 5, a VL CDR1 having the sequence as set forth in SEQ ID NO: 28, a VL CDR2 having the sequence as set forth in SEQ ID NO: 29, and a VL CDR3 having the sequence as set forth in SEQ ID NO: 30, (iii) a VH CDR1 having the sequence as set forth in SEQ ID NO: 8, a VH CDR2 having the sequence as set forth in SEQ ID NO: 9, a VH CDR3 having the sequence as set forth in SEQ ID NO: 10, a VL CDR1 having the sequence as set forth in SEQ ID NO: 33, a VL CDR2 having the sequence as set forth in SEQ ID NO: 34, and a VL CDR3 having the sequence as set forth in SEQ ID NO: 35, (iv) a VH CDR1 having the sequence as set forth in SEQ ID NO: 13, a VH CDR2 having the sequence as set forth in SEQ ID NO: 14, a VH CDR3 having the sequence as set forth in SEQ ID NO: 15, a VL CDR1 having the sequence as set forth in SEQ ID NO: 38, a VL CDR2 having the sequence as set forth in SEQ ID NO: 39, and a VL CDR3 having the sequence as set forth in SEQ ID NO: 40, (v) a VH CDR1 having the sequence as set forth in SEQ ID NO: 18, a VH CDR2 having the sequence as set forth in SEQ ID NO: 19, a VH CDR3 having the sequence as set forth in SEQ ID NO: 20, a VL CDR1 having the sequence as set forth in SEQ ID NO: 43, a VL CDR2 having the sequence as set forth in SEQ ID NO: 44, and a VL CDR3 having the sequence as set forth in SEQ ID NO: 45, or (vi) a VH CDR1 having the sequence as set forth in SEQ ID NO: 23, a VH CDR2 having the sequence as set forth in SEQ ID NO: 24, a VH CDR3 having the sequence as set forth in SEQ ID NO: 25, a VL CDR1 having the sequence as set forth in SEQ ID NO 48, a VL CDR2 having the sequence as set forth in SEQ ID NO: 49, and a VL CDR3 having the sequence as set forth in SEQ ID NO: 50, an immunoconjugate comprising the antibody, or a bispecific antibody comprising the antibody. 3. The method according to claim 2, wherein the disease or disorder is rheumatoid arthritis. 4. The method according to claim 2, wherein the disease or disorder is selected from the group consisting of: chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), mantle cell lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. 5. The method according to claim 2, wherein the disease or disorder is multiple myeloma. 6. The method according to claim 2, wherein the method comprises administering one or more further therapeutic agents to the subject. 7. The method according to claim 6, wherein the one or more further therapeutic agents are selected from the group consisting of: a chemotherapeutic agent, an anti-inflammatory agent, an immunosuppressive agent, and an immunomodulatory agent. 8. The method according to claim 6, wherein the one or more further therapeutic agents are selected from a group consisting of cisplatin, gefitinib, cetuximab, rituximab, ofatumumab, bevacizumab, erlotinib, bortezomib, thalidomide, pamidronate, zoledronic acid, clodronate, risendronate, ibandronate, etidronate, alendronate, tiludronate, arsenic trioxide, lenalidomide, dexamethasone, prednisolone, filgrastim, pegfilgrastim, sargramostim, suberoylanilide hydroxamic acid, and SCIO-469. 9. The method of claim 2, wherein the antibody binds to a variant of human CD38 having a single amino acid substitution wherein Gln in position 272 has been substituted with Arg to the same degree that it binds to human CD38, and binds to a variant of human CD38 having a single amino acid substitution wherein the Ser in position 274 has been substituted with Phe to the same degree that it binds to human CD38. 10. The method of claim 2, wherein the antibody binds human CD38 and has an inhibitory effect on CD38 cyclase activity and a stimulatory effect on CD38 hydrolase activity. 11. The method of claim 10, wherein the inhibitory effect is at least 50-66% compared to the inhibitory effect on CD38 cyclase activity in the absence of antibody. 12. The method of claim 2, wherein the antibody inhibits the ability of CD38 to catalyze the formation, via a base-exchange reaction, of NAADP with an IC50 of below 0.5 .mu.g/mL. 13. The method of claim 2, wherein the antibody is capable of inducing antibody-dependent cellular cytotoxicity (ADCC). 14. The method of claim 2, wherein the antibody induces ADCC in Daudi cells. 15. The method of claim 2, wherein the antibody is not capable of inducing complement-dependent cytotoxicity (CDC) in Daudi cells. 16. The method of claim 1, wherein the antibody comprises (i) a VH region comprising the sequence as set forth in SEQ ID NO: 2, and a VL region comprising the sequence as set forth in SEQ ID NO: 27, (ii) a VH region comprising the sequence as set forth in SEQ ID NO: 7, and a VL region comprising the sequence as set forth in SEQ ID NO: 32, (iii) a VH region comprising the sequence as set forth in SEQ ID NO: 12, and a VL region comprising the sequence as set forth in SEQ ID NO: 37, (iv) a VH region comprising the sequence as set forth in SEQ ID NO: 17, and a VL region comprising the sequence as set forth in SEQ ID NO: 42, or (v) a VH region comprising the sequence as set forth in SEQ ID NO: 22, and a VL region comprising the sequence as set forth in SEQ ID NO: 47. 17. The method of claim 2, wherein the antibody is a human monovalent antibody. 18. The method of claim 2, wherein the antibody is a full length IgG1, IgG2, IgG3, IgG4, IgD, IgA, IgE, or IgM antibody. 19. The method of claim 2, wherein the antibody is an antibody fragment or a single-chain antibody. 20. The method of claim 2, wherein the antibody is conjugated to a cytotoxic agent, a radioisotope, or a drug. 21. The method of claim 20, wherein the antibody is conjugated to an auristatin or a functional peptide analog or derivate thereof via a linker. 22. The method of claim 2, wherein the bispecific antibody comprises a second binding specificity for a human effector cell or a cancer antigen. 23. The method of claim 22, wherein the second binding specificity is for a human Fc receptor or for a T cell receptor. 24. The method of claim 2, wherein the antibody comprises (i) a VH region comprising the sequence as set forth in SEQ ID NO: 2, and a VL region comprising the sequence as set forth in SEQ ID NO: 27, (ii) a VH region comprising the sequence as set forth in SEQ ID NO: 7, and a VL region comprising the sequence as set forth in SEQ ID NO: 32, (iii) a VH region comprising the sequence as set forth in SEQ ID NO: 12, and a VL region comprising the sequence as set forth in SEQ ID NO: 37, (iv) a VH region comprising the sequence as set forth in SEQ ID NO: 17, and a VL region comprising the sequence as set forth in SEQ ID NO: 42, or (v) a VH region comprising the sequence as set forth in SEQ ID NO: 22, and a VL region comprising the sequence as set forth in SEQ ID NO: 47. 25. The method of claim 2, wherein the cancer is selected from the group consisting of a B-cell neoplasm, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), acute myelogenous leukemia, non-small cell lung cancer, T-cell malignancy, NK-cell malignancy, and myeloid cell malignancy. 26. The method of claim 25, wherein the B-cell neoplasm is selected from the group consisting of: small lymphocytic lymphoma, B-cell prolymphocytic lymphoma, B-cell chronic lymphocytic leukemia, mantle cell lymphoma, Burkitt's lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, multiple myeloma, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, plasma cell leukemia, monoclonal immunoglobulin deposition disease, heavy chain disease, MALT lymphoma, nodal marginal B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, non-Hodgkins lymphoma, Hodgkins lymphoma, hairy cell leukemia, primary effusion lymphoma, AIDS-related non-Hodgkins lymphoma, precursor B cell lymphoblastic leukemia, precursor B cell lymphoblastic lymphoma, acute promyelocytic leukemia, acute lymphoblastic leukemia, B cell acute lymphocytic leukemia, cutaneous follicle center lymphoma, post-transplant lymphoproliferative disorder, Waldenstrom's macroglobulinemia, and anaplastic large-cell lymphoma. 27. The method of claim 26, wherein the non-Hodgkin's lymphoma is selected from the group consisting of: lymphomatoid granulomatosis, primary effusion lymphoma, intravascular large B cell lymphoma, mediastinal large B cell lymphoma, heavy chain diseases, lymphomas induced by therapy with immunosuppressive agents, and methotrexate-induced lymphoma. 28. The method of claim 25, wherein the T-cell or NK-cell malignancy is selected from the group consisting of: mature T cell and NK cell neoplasms including T cell prolymphocytic leukemia, T cell large granular lymphocytic leukemia, aggressive NK cell leukemia, adult T cell leukemia/lymphoma, extranodal NK/T cell lymphoma, nasal type, enteropathy-type T cell lymphoma, hepatosplenic T cell lymphoma, subcutaneous panniculitis-like T cell lymphoma, blastic NK cell lymphoma, Mycosis Fungoides/Sezary Syndrome, primary cutaneous CD30 positive T cell lymphoproliferative disorders, angioimmunoblastic T cell lymphoma, peripheral T cell lymphoma unspecified, and anaplastic large cell lymphoma. 29. The method of claim 25, wherein the myeloid cell malignancy is selected from the group consisting of: acute myeloid leukemia, including acute promyelocytic leukemia, and chronic myeloproliferative diseases, including chronic myeloid leukemia. 30. The method of claim 2, wherein the inflammatory disorder, immune disorder, or autoimmune disorder is selected from the group consisting of: psoriasis, psoriatic arthritis, dermatitis, systemic scleroderma and sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, respiratory distress syndrome, meningitis, encephalitis, uveitis, glomerulonephritis, eczema, asthma, atherosclerosis, leukocyte adhesion deficiency, multiple sclerosis, Raynaud's syndrome, Sjogren's syndrome, juvenile onset diabetes, Reiter's disease, Behcet's disease, immune complex nephritis, IgA nephropathy, IgM polyneuropathies, immune-mediated thrombocytopenias, hemolytic anemia, myasthenia gravis, lupus nephritis, systemic lupus erythematosus, atopic dermatitis, pemphigus, Graves' disease, Hashimoto's thyroiditis, Wegener's granulomatosis, Omenn's syndrome, chronic renal failure, acute infectious mononucleosis, multiple sclerosis, HIV, herpes virus-associated diseases, severe acute respiratory distress syndrome, choreoretinitis, and diseases and disorders caused or mediated by infection of B-cells with virus. 31. The method of claim 2, wherein the inflammatory disorder, immune disorder, or autoimmune disorder is selected from the group consisting of: vasculitides, vessel disorders, skin disorders, immune-mediated cytopenias, connective tissue disorders, hematologic disorders, endocrinopathies, hepato-gastrointestinal disorders, neurological disorders, nephropathies, multiple sclerosis, cardiac and pulmonary disorders, allergic disorders, ophthalmologic disorders, infectious diseases, gynecological-obstretical disorders, male reproductive disorders, and transplantation-derived disorders. 32. The method of claim 31, wherein the inflammatory disorder, immune disorder, or autoimmune disorder is selected from the group consisting of: microscopic polyangiitis, Churg-Strauss syndrome, ANCA-associated vasculitides, polyarteritis nodosa, essential cryoglobulinaemic vasculitis, cutaneous leukocytoclastic angiitis, Kawasaki disease, Takayasu arteritis, giant cell arthritis, Henoch-Schonlein purpura, primary or isolated cerebral angiitis, erythema nodosum, thrombangiitis obliterans, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, secondary vasculitides, cutaneous leukocytoclastic vasculitis secondary to hepatitis B, hepatitis C, Waldenstrom's macroglobulinemia, B-cell neoplasias, rheumatoid arthritis, Sjogren's syndrome, or systemic lupus erythematosus, erythema nodosum, allergic vasculitis, panniculitis, Weber-Christian disease, purpura hyperglobulinaemica, Buerger's disease, contact dermatitis, linear IgA dermatosis, vitiligo, pyoderma gangrenosum, epidermolysis bullosa acquisita, pemphigus vulgaris, cicatricial pemphigoid, bullous pemphigoid, alopecia greata, alopecia universalis alopecia totalis, dermatitis herpetiformis, erythema multiforme, and chronic autoimmune urticarial, angioneurotic edema, urticarial vasculitis, autoimmune neutropenia, pure red cell aplasia, CNS lupus, discoid lupus erythematosus, CREST syndrome, mixed connective tissue disease, polymyositis/dermatomyositis, inclusion body myositis, secondary amyloidosis, cryoglobulinemia type I and type II, fibromyalgia, phospholipid antibody syndrome, secondary hemophilia, relapsing polychondritis, sarcoidosis, stiff man syndrome, rheumatic fever, eosinophil fasciitis, ankylosing spondylitis, juvenile chronic arthritis, adult Still's disease, SAPHO syndrome, sacroileitis, reactive arthritis, Still's disease, gout, aplastic anemia, primary hemolytic anemia, hemolytic anemia secondary to CLL or systemic lupus erythematosus, POEMS syndrome, pernicious anemia, Waldemstrom's purpura hyperglobulinaemica, agranulocytosis, autoimmune neutropenia, Franklin's disease, Seligmann's disease, gamma heavy chain disease, paraneoplastic syndrome secondary to thymoma and lymphomas, paraneoplastic syndrome secondary to thymoma and lymphomas, and factor VIII inhibitor formation, polyendocrinopathy, Addison's disease, autoimmune hypoglycemia, autoimmune hypothyroidism, autoimmune insulin syndrome, de Quervain's thyroiditis, insulin receptor antibody-mediated insulin resistance, celiac disease, Whipple's disease, primary biliary cirrhosis, chronic active hepatitis, primary sclerosing cholangitis, autoimmune gastritis, rapid progressive glomerulonephritis, post-streptococcal nephritis, Goodpasture's syndrome, membranous glomerulonephritis, cryoglobulinemic nephritis, minimal change disease, autoimmune neuropathies, mononeuritis multiplex, Lambert-Eaton's myasthenic syndrome, Sydenham's chorea, tabes dorsalis, Guillain-Barre's syndrome, myelopathy/tropical spastic paraparesis, myasthenia gravis, acute inflammatory demyelinating polyneuropathy, chronic inflammatory demyelinating polyneuropathy, COPD, fibrosing alveolitis, bronchiolitis obliterans, allergic aspergillosis, cystic fibrosis, Loffler's syndrome, myocarditis, pericarditis, hypersensitivity pneumonitis, paraneoplastic syndrome secondary to lung cancer, bronchial asthma, hyper-IgE syndrome, amaurosis fugax, idiopathic chorioretinitis, parvovirus B infection, hands-and-socks syndrome, recurrent abortion, recurrent fetal loss, intrauterine growth retardation, paraneoplastic syndrome secondary to gynecological neoplasms, paraneoplastic syndrome secondary to testicular neoplasms, allograft rejection, xenograft rejection, and graft-versus-host disease. 33. The method of claim 4, wherein the disease is chronic lymphocytic leukemia. 34. The method of claim 4, wherein the disease is acute lymphoblastic leukemia. 35. The method of claim 4, wherein the disease is acute myelogenous leukemia. 36. The method of claim 4, wherein the disease is mantle cell lymphoma. 37. The method of claim 4, wherein the disease is follicular lymphoma. 38. The method of claim 4, wherein the disease is diffuse large B-cell lymphoma. 39. The method of claim 26, wherein the B-cell neoplasm is plasma cell myeloma. 40. The method of claim 26, wherein the B-cell neoplasm is non-Hodgkins lymphoma. 41. The method of claim 26, wherein the B-cell neoplasm is Hodgkins lymphoma. 42. The method of claim 30, wherein the disorder is glomerulonephritis. 43. The method of claim 30, wherein the disorder is systemic lupus erythematosus. 44. The method of claim 32, wherein the disorder is Waldenstrom's macroglobulinemia. 45. The method of claim 32, wherein the disorder is secondary amyloidosis. 46. The method of claim 32, wherein the disorder is allograft rejection. 47. The method of claim 32, wherein the disorder is xenograft rejection. 48. The method of claim 32, wherein the disorder is graft-versus-host disease.

Details for Patent 9,944,711

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Amgen, Inc.	NEUPOGEN	filgrastim	Injection	103353	02/20/1991		2030-06-09
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