Enhanced B cell cytotoxicity of CDIM binding antibody

• US 20050112130A1
• Filed: 11/05/2004
• Published: 05/26/2005
• Est. Priority Date: 11/05/2003
• Status: Abandoned Application

• Current Assignee: Palingen, Inc., Board of Trustees of the Leland Stanford Junior University (Stanford University)
• Original Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford University)
• Inventors: Bieber, Marcia M., Sanders, Martin E., Teng, Nelson N.H., Bhat, Neelima M.
• Application Number:
  US10/982,698
• Publication Number:
  US 20050112130A1
• Time in Patent Office: Days
• US Class Current: 424/155.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/475 having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine vincamine A61K31/4375
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• 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 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/38 : of the suprarenal hormones
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 16/28 : against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/2887 : against CD20
• CPC Class Codes: C07K 16/3061 : Blood cells
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man

Abstract

Formulations and methods of treating human patients suffering from a condition characterized by lymphoid cancer, autoimmune disease or B cell hyperproliferation are disclosed, the treatment comprising administering (1) a cytotoxic amount of an antibody having specific binding for CDIM epitopes on a B cell, and (2) a cytotoxic agent, including a chemotherapeutic agent, radioactive isotope, cytotoxic antibody, immunoconjugate, ligand conjugate, immunosuppressant, cell growth regulator and/or inhibitor, toxin, or mixtures thereof, including agents that disrupt the cytoskeleton of B cells, particularly vinca alkaloids or colchicine.

Claims

1. A method of treating a human patient suffering from a condition characterized by a hyperproliferation of B cells, comprising contacting said B cells with (1) a cytotoxic amount of an antibody having specific binding for CDIM epitopes on a B cell, and (2) a cytotoxic agent.

2. The method of claim 1, wherein the condition characterized by a hyperproliferation of B cells is lymphoid cancer, viral infection, immunodeficiency, or autoimmune disease.

3. The method of claim 2, wherein said viral infection is human immunodeficiency virus or mononucleosis.

4. The method of claim 2, wherein said immunodeficiency is post-transplant lymphoproliferative disease, or immunodeficiency syndrome

5. The method of claim 2, wherein said autoimmune disease is systemic lupus erythematosis, rheumatoid arthritis, autoimmune lymphoproliferative disease, multiple sclerosis, psoriasis, myasthenia gravis, Hashimoto'"'"'s thyroiditis, Alzheimer'"'"'s disease, lupus nephritis, Class III autoimmune diseases such as immune-mediated thrombocytopenias, such as acute idiopathic thrombocytopenic purpura and chronic idiopathic thrombocytopenic purpura, dermatomyositis, Sjogren'"'"'s syndrome, multiple sclerosis, Sydenham'"'"'s chorea, myasthenia gravis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, polyglandular syndromes, bullous pemphigoid, diabetes mellitus, Henoch-Schonlein purpura, post-streptococcal nephritis, erythema nodosum, Takayasu'"'"'s arteritis, Addison'"'"'s disease, Crohn'"'"'s disease, sarcoidosis, ulcerative colitis, erythema multiforme, IgA nephropathy, polyarteritis nodosa, ankylosing spondylitis, Goodpasture'"'"'s syndrome, thromboangitis ubiterans, primary biliary cirrhosis, thyrotoxicosis, scleroderma, chronic active hepatitis, polymyositis/dermatomyositis, polychondritis, pamphigus vulgaris, Wegener'"'"'s granulomatosis, membranous nephropathy, amyotrophic lateral sclerosis, tabes dorsalis, giant cell arteritis/polymyalgia, pernicious anemia, rapidly progressive glomerulonephritis and fibrosing alveolitis,.

6. The method of claim 1, wherein the cytotoxic agent is a chemotherapeutic agent, a radioactive isotope, a cytotoxic antibody, an immunoconjugate, a ligand conjugate, an immunosuppressant, a cell growth regulator and/or inhibitor, a toxin, or mixtures thereof.

7. The method of claim 6, wherein the chemotherapeutic agent is an agent that disrupts the cytoskeleton of the B cell.

8. The method of claim 7, wherein the agent that disrupts the cytoskeleton of the B cell is an agent that interferes with the polymerization or depolymerization of microtubules.

9. The method of claim 8, wherein the agent that interferes with the polymerization or depolymerization of microtubules is a taxane, vinca alkaloid or colchicine, or mixtures thereof.

10. The method of claim 9, wherein the vinca alkaloid is vinblastine, vincristine, vindesine, or vinorelbine, or mixtures thereof.

11. The method of claim 9, wherein the taxane is paclitaxel, or docetaxel, or mixtures thereof.

12. The method of claim 8, wherein the agent that disrupts the cytoskeleton of the B cell is an anti-actin agent.

13. The method of claim 6, wherein the chemotherapeutic agent is asparaginase, epipodophyllotoxin, camptothecin, antibiotic, platinum coordination complex, alkylating agent, folic acid analog, pyrimidine analog, purine analog or topoisomerase inhibitor, or mixtures thereof.

14. The method of claim 13, wherein the topoisomerase inhibitor is an epipodophyllotoxin.

15. The method of claim 13, wherein the epipodophyllotoxin is etoposide or teniposide.

16. The method of claim 13, wherein the pyrimidine analog is capecitabine, 5-fluoruracil, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, cytosine arabinoside, 5-azacytidine, 2′

, 2′

-difluorodeoxycytidine.

17. The method of claim 13, wherein the purine analog is mercaptopurine, azathioprene, thioguanine, pentostatin, erythrohydroxynonyladenine, cladribine, vidarabine, fludarabine phosphate.

18. The method of claim 13, wherein the folic acid analog is methotrexate, raltitrexed, lometrexol, permefrexed, edatrexate, pemetrexed.

19. The method of claim 13, wherein the camptothecin is irinotocan, topotecan, camptothecan.

20. The method of claim 13, wherein the antibiotic is dactinomycin, daunorubicin, doxorubicin, idarubicin, epirubicin, valrubucin, mitoxanthrone, bleomycin, or mitomycin.

21. The method of claim 13, wherein the platinum coordination complex is cisplatin, carboplatin, or oxaliplatin.

22. The method of claim 13, wherein the alkylating agent is mechlorethamine, cyclophosphamide, ifosfamide, melphalan, dacarbazine, temozolomide, thiotepa, hexamethylmelamine, streptozocin, carmustine, busulfan, altretamine or chlorambucil.

23. The method of claim 1, wherein the cytotoxic agent is administered simultaneously with, before or after administration of the antibody having specific binding for CDIM epitopes on a B cell.

24. The method of claim 1, wherein the cytotoxic agent is covalently or noncovalently attached to the antibody having specific binding for CDIM epitopes on a B cell.

25. The method of claim 1, wherein the antibody having specific binding for CDIM epitopes on a B cell is a VH4-34 encoded antibody.

26. The method of claim 25, wherein the antibody having specific binding for CDIM epitopes on a B cell is mAb 216, RT-2B, FS 12, A6(H4C5), Cal-4G, S20A2, FS 3, Gee, HT, Z2D2, Y2K.

27. The method of claim 26, wherein the antibody having specific binding for CDIM epitopes on a B cell is mAB 216.

28. The method of claim 1, wherein the antibody having specific binding for CDIM epitopes on a B cell comprises a CDR sequence having a net positive charge.

29. The method of claim 6, wherein the cytotoxic agent is a radioactive isotope.

30. The method of claim 29, wherein the radioactive isotope is ¹³¹I, ¹²⁵I, ¹²³I, ⁹⁰Y, ¹¹¹In, ¹⁰⁵Rh, ¹⁵³Sm, ⁶⁷Cu, ⁶⁷Ga, ¹⁶⁶Ho, ¹⁷⁷Lu, ¹⁸⁸Re or ¹⁸⁶Re.

31. The method of claim 6, wherein the cytotoxic antibody has specific binding for a cell surface receptor on a B cell.

32. The method of claim 31, wherein the cytotoxic antibody has specific binding for CD11a, CD19, CD20, CD21, CD22, CD25, CD34, CD37, CD38, CD40, CD45, CD52, CD80, CD 86, IL4R, IL-6R, IL-8R, IL-13, IL-13R, α

-4/β

-1 integrin (VLA4), BLYS receptor, cell surface idiotypic Ig, tumor necrosis factor (TNF), or mixtures thereof.

33. The method of claim 31, wherein the cytotoxic antibody is efalizumab (RAPTIVA), rituximab (RITUXAN), daclizumab (ZENAPAX), epratuzumab, basiliximab (SIMULECT), anti-CD52 (CAMPATH), natalizumab, or infliximab (REMICADE).

34. The method of claim 31, wherein the cytotoxic antibody is an immunoconjugate.

35. The method of claim 6, wherein the cytotoxic agent is a ligand conjugate.

36. The method of claim 35, wherein the ligand conjugate comprises IL-2, IL-4, IL-6, IL-13, IL-15, BLYS, or TNF.

37. The method of claim 6, wherein the immunosuppressant is a glucocorticoid, a calcineurin inhibitor, an antiproliferative/antimetabolic agent, or an immunosuppressive antibody.

38. The method of claim 37, wherein the calcineurin inhibitor is cyclosporine or tacrolimus.

39. The method of claim 37, wherein the antiproliferative/antimetabolic agent is azathioprine, chlorambucol, cyclophosphamide, leflunomide, mycophenolate mofetil, methotrexate, rapamycin, thalidomide, or mixtures thereof.

40. The method of claim 37, wherein the glucocorticoid is selected from prednisolone, prednisone, or dexamethasone.

41. The method of claim 37, wherein the cell growth regulator and/or inhibitor is a small molecule therapeutic agent, gene therapy agent or gene expression modifier.

42. The method of claim 41, wherein the small molecule therapeutic agent is a kinase inhibitor, or a proteasome inhibitor.

43. The method of claim 42, wherein the kinase inhibitor is a bcr/abl tyrosine kinase inhibitor, or a tyrosine kinase inhibitor.

44. The method of claim 42, wherein the proteasome inhibitor is a boronic ester.

45. The method of claim 41, wherein the gene therapy agent is a plasmid, naked DNA, or nucleic acid-peptide complex.

46. The method of claim 41, wherein the gene expression modifier is an antisense nucleic acid, or interfering nucleic acid (e.g., RNAi).

47. The method of claim 6, wherein the toxin is Pseudomonas exotoxin A, ricin, diphtheria toxin, momordin, pokeweed antiviral protein, Staphylococcal enterotoxin A, gelonin, or a maytansinoid.

48. The method of claim 2, wherein said lymphoid cancer is any acute or chronic leukemia or lymphoma of B cell origin.

49. The method of claim 2, wherein the lymphoid cancer is acute lymphocytic leukemia (ALL), non-Hodgkins lymphoma (NHL), Burkitt'"'"'s lymphoma, B progenitor ALL, adult ALL, or chronic lymphocytic leukemia (CLL).

50. The method of claim 1, wherein said contacting is performed in vivo, in vitro or ex vivo.

51. The method of claim 50, wherein said in vivo contacting is performed by administering said antibody having specific binding for CDIM epitopes on a B cell by parenteral injection to the human patient.

52. A method of treating a human patient suffering from a condition characterized by lymphoid cancer, comprising administering (1) a cytotoxic amount of an antibody having specific binding for CDIM epitopes on a B cell, and (2) a chemotherapeutic agent.

53. A method of treating a human patient suffering from a condition characterized by lymphoid cancer, comprising administering (1) a cytotoxic amount of an antibody having specific binding for CDIM epitopes on a B cell, and (2) a cytotoxic antibody having specific binding for a cell surface receptor on a B cell.

54. A method of augmenting the B cell cytotoxicity of an antibody that binds a CDIM epitope, comprising contacting B cells with the antibody that binds a CDIM epitope and an agent that disrupts the cytoskeleton of B cells.

55. The method of claim 54, wherein the agent that disrupts the cytoskeleton of B cells is an agent that interferes with the polymerization or depolymerization of microtubules.

56. The method of claim 55, wherein the agent that interferes with the polymerization or depolymerization of microtubules is a taxane, vinca alkaloid or colchicine.

57. The method of claim 56, wherein the vinca alkaloid is vinblastine, vincristine, vindesine, or vinorelbine.

58. The method of claim 56, wherein the taxane is paclitaxel, or docetaxel.

59. The method of claim 54, wherein the method of augmenting B cell cytotoxicity is used in the therapy of lymphoid cancer, B cell hyperproliferative diseases, or autoimmune disease.

60. A method of treating an autoimmune disease in a mammal, comprising administering (1) a cytotoxic amount of an antibody having specific binding for CDIM epitopes on a B cell, and (2) a chemotherapeutic agent, an antibody having specific binding for cell surface receptors on a B cell, an immunosuppressant, a cell growth regulator and/or inhibitor, or mixtures thereof.

61. A method of killing malignant B cells that are resistant to chemotherapeutic agents, cell growth regulators and/or inhibitors, or cytotoxic antibodies, comprising contacting said malignant B cells with an antibody having specific binding for CDIM epitopes on a B cell.

62. The method of claim 61, further comprising contacting said malignant B cells with an additional chemotherapeutic agent.

63. A method of killing malignant B cells that are resistant to an antibody having specific binding for CDIM epitopes on a B cell, comprising treating said B cells with a chemotherapeutic agent and an antibody having specific binding for CDIM epitopes on the B cells.

64. A method of treating a disease or disorder characterized by a hyperproliferation of B cells, comprising contacting the B cells with an amount of an antibody having specific binding for CDIM epitopes on a B cell sufficient to permeabilize the B cells.

65. A method for reducing tumor load in a patient suffering from lymphoid cancer refractory to reinduction therapy, comprising administering a cytotoxic amount of an antibody having specific binding for CDIM epitopes on a B cell, wherein said treatment allows the patient to undergo subsequent reinduction therapy.

66. A method for augmenting the cytotoxicity of an anti-B cell antibody, comprising administering a cytotoxic amount of an antibody having specific binding for CDIM epitopes on a B cell.

67. A pharmaceutical formulation for parenteral injection comprising a cytotoxic amount of an antibody having specific binding for CDIM epitopes on a B cell.

68. The pharmaceutical formulation of claim 67, further comprising a chemotherapeutic agent.

69. A kit for treating a patient suffering from a condition characterized by a hyperproliferation of B cells comprising:

(a) an amount of an antibody having specific binding for CDIM epitopes on a B cell sufficient to permeabilize the B cells in the patient,

(b) a therapeutically effective amount of a cytotoxic agent effective to treat the condition characterized by the hyperproliferation of B cells.

70. A method for purging the bone marrow of a patient suffering from lymphoid cancer of malignant B cells prior to reimplantation of the bone marrow in the patient after myeloablative therapy, comprising treating the bone marrow ex vivo with a cytotoxic amount of an antibody having specific binding for CDIM epitopes on a B cell.

71. The method of claim 70, further comprising treating the bone marrow with a cytotoxic agent.

72. A method for treating a human patient suffering from a condition characterized by hyperproliferation of B cells, comprising contacting said B cells with (1) a cytotoxic amount of the anti-CDIM antibody mAb 216 or Y2K, and (2) an anti-CD20 antibody.

73. The method of claim 72, wherein the anti-CD20 antibody is rituximab, tosutimab or ibritumomab.

74. The method of claim 72, further comprising contacting the B cells of the patient with vincristine or vinblastine.

75. A method for treating a human patient suffering from a condition characterized by hyperproliferation of B cells, comprising contacting said B cells with (1) a cytotoxic amount of the anti-CDIM antibody mAb 216 or Y2K, and (2) an anti-CD52 antibody.

76. The method of claim 75, wherein the anti-CD52 antibody is CAMPATH.

77. The method of claim 75, further comprising contacting the B cells of the patient with vincristine or vinblastine.

78. A method for treating a human patient suffering from a condition characterized by hyperproliferation of B cells, comprising contacting said B cells with (1) a cytotoxic amount of the anti-CDIM antibody mAb 216 or Y2K, and (2) an anti-CD22 antibody.

79. The method of claim 78, wherein the anti-CD22 antibody is epratuzumab.

80. The method of claim 78, further comprising contacting the B cells of the patient with vincristine or vinblastine.