Combination therapy for B cell disorders

• US 20050095243A1
• Filed: 06/04/2004
• Published: 05/05/2005
• Est. Priority Date: 06/05/2003
• Status: Abandoned Application

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Martin, Flavius, Gong, Qian, Chan, Andrew
• Application Number:
  US10/861,049
• Publication Number:
  US 20050095243A1
• Time in Patent Office: Days
• US Class Current: 424/144.1
• CPC Class Codes: A61K 2039/505 comprising 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 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 39/39541 against normal tissues, cells
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• 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 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 : for peripheral neuropathies
• 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 31/00 : 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 31/14 : for RNA viruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/20 : for DNA viruses
• CPC Class Codes: A61P 31/22 : for herpes viruses
• 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 35/02 : specific for leukemia
• 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 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 16/2875 : against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 against NGF C07K16/22, against TNF C07K16/241
• CPC Class Codes: C07K 16/2887 : against CD20
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/55 : Fab or Fab'
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 7/06 : having 5 to 11 amino acids
• CPC Class Codes: C07K 7/08 : having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68

Abstract

The invention provides methods of treating B cell based malignancies and B-cell regulated autoimmune disorders using a combination therapy of anti-CD20 antibody with a BLyS antagonist.

Claims

1. A method of depleting B cells from a mixed population of cells comprising contacting the mixed population of cells with a BLyS antagonist and a CD20 binding antibody.

2. The method of claim 1 wherein the B cells are human B cells and the mixed population of cells are contacted with a BLyS antagonist and the CD20 binding antibody in vivo.

3. The method of claim 1 wherein the BLyS antagonist is an immunoadhesin.

4. The method of claim 3, wherein the immunoadhesin is selected from the group consisting of BR3 immunoadhesin comprising the extracellular domain of BR3, TACI immunoadhesin comprising the extracellular domain of TACI, and BCMA immunoadhesin comprising the extracellular domain of BCMA.

5. The method of claim 4, wherein the BR3 immunoadhesin is BR3-Fc of SEQ ID No. 2.

6. The method of claim 1, wherein the BLyS antagonist is an anti-BLyS antibody.

7. The method of claim 6, wherein the anti-BLyS antibody binds BLyS within a region of BLyS comprising residues 162-275.

8. The method of claim 1, wherein the BLyS antagonist is an anti-BR3 antibody.

9. The method of claim 8, wherein the anti-BR3 antibody binds BR3 in a region comprising residues 23-38 of human BR3.

10. The method of claim 1, wherein the anti-CD20 antibody is Rituxan™

.

11. The method of claim 1, wherein the anti-CD20 antibody is hu2H7v.16 having the light and heavy chain sequence of SEQ ID NO.15 and SEQ ID NO.16, respectively.

12. The method of claim 1 wherein the BLyS antagonist and the anti-CD20 antibody act synergistically to deplete the B cells.

25. The method of claim 8, wherein the anti-BR3 antibody binds BR3 in a region comprising residues 23-38 of human BR3.

53. The method of any one of claims 1, 13, 34 and 52, wherein the BLyS antagonist is selected from the group consisting of a polypeptide having the sequence of SEQ ID NO. 5, SEQ ID NO. 6, SEQ ID NO.7 SEQ ID NO. 8, SEQ ID NO. 9, or SEQ ID NO. 10.

13. A method of treating a B cell neoplasm or malignancy characterized by B cells expressing CD20, comprising administering to a patient suffering from the neoplasm or malignancy, a therapeutically effective amount of a CD20 binding antibody and of a BLyS antagonist.

14. The method of claim 13, wherein the CD20 binding antibody and BLyS antagonist are administered concurrently.

15. The method of claim 13, wherein the CD20 binding antibody and BLyS antagonist are administered sequentially.

16. The method of claim 13, wherein the BLyS antagonist is administered before the CD20 binding antibody.

17. The method of claim 13, wherein the B cell neoplasm is non-Hodgkin'"'"'s lymphoma (NHL), small lymphocytic (SL) NHL, lymphocyte predominant Hodgkin'"'"'s disease (LPHD), follicular center cell (FCC) lymphomas, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL) and Hairy cell leukemia.

18. The method of claim 17, wherein the B cell neoplasm is non-Hodgkin'"'"'s lymphoma (NHL) or small lymphocytic (SL) NHL.

19. The method of claim 13, wherein the BLyS antagonist is an immunoadhesin.

20. The method of claim 19, wherein the immunoadhesin is selected from the group consisting of BR3 immunoadhesin comprising the extracellular domain of BR3, TACI immunoadhesin comprising the extracellular domain of TACI, and BCMA immunoadhesin comprising the extracellular domain of BCMA.

21. The method of claim 20, wherein the BR3 immunoadhesin is hBR3-Fc of SEQ ID NO. 2.

22. The method of claim 13, wherein the BLyS antagonist is an anti-BLyS antibody.

23. The method of claim 14, wherein the anti-BLyS antibody binds BLyS within a region of BLyS comprising residues 162-275.

24. The method of claim 13, wherein the BLyS antagonist is an anti-BR3 antibody.

26. The method of claim 13, wherein the CD20 binding antibody is a chimeric antibody comprising the variable regions from a murine antibody fused to the constant regions of a human antibody.

27. The method of claim 26, wherein the chimeric antibody is Rituxan™

.

28. The method of claim 13, wherein the CD20 binding antibody is a humanized antibody.

29. The method of claim 28, wherein the humanized antibody is hu2H7v.16 having the light and heavy chain sequence of SEQ ID NO.15 and SEQ ID NO.16, respectively.

30. The method of claim 21, wherein the CD20 binding antibody is Rituxan™

or hu2H7v.16 having the light and heavy chain sequence of SEQ ID NO.15 and SEQ ID NO.16, respectively.

31. The method of claim 30, wherein BR3-Fc is administered at a dosage of about 2-5 mg/kg and Rituxan is administered at a dosage of about 375 mg/m².

32. The method of claim 13, wherein administration of the BLyS antagonist and the CD20 binding antibody produces a synergistic effect to deplete the B cells.

33. The method of claim 13, wherein the BLyS antagonist and the CD20 binding antibody are administered in conjunction with chemotherapy.

47. The method of claim 28, wherein the humanized antibody is hu2H7v.16 having the light and heavy chain sequence of SEQ ID NO.15 and SEQ ID NO.16, respectively.

34. A method of alleviating a B-cell regulated autoimmune disorder comprising administering to a patient suffering from the disorder, a therapeutically effective amount of a CD20 binding antibody and of a BLyS antagonist.

35. The method of claim 34, wherein the CD20 binding antibody and BLyS antagonist are administered sequentially.

36. The method of claim 34, wherein the BLyS antagonist is administered before the CD20 binding antibody.

37. The method of claim 34, wherein the autoimmune disorder is selected from the group consisting of rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus (SLE), Wegener'"'"'s disease, inflammatory bowel disease, idiopathic thrombocytopenic purpura (ITP), thrombotic throbocytopenic purpura (TTP), autoimmune thrombocytopenia, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, myasthenia gravis, vasculitis, diabetes mellitus, Reynaud'"'"'s syndrome, Sjorgen'"'"'s syndrome and glomerulonephritis.

38. The method of claim 37, wherein the autoimmune disorder is rheumatoid arthritis and systemic lupus erythematosus.

39. The method of claim 34, wherein the BLyS antagonist is an immunoadhesin.

40. The method of claim 39, wherein the immunoadhesin is selected from the group consisting of BR3 immunoadhesin comprising the extracellular domain of BR3, TACI immunoadhesin comprising the extracellular domain of TACI, and BCMA immunoadhesin comprising the extracellular domain of BCMA.

41. The method of claim 40, wherein the BR3 immunoadhesin is BR3-Fc of SEQ ID No. 2.

42. The method of claim 34, wherein the BLyS antagonist is an anti-BLyS antibody.

43. The method of claim 34, wherein the BLyS antagonist is an anti-BR3 antibody.

44. The method of claim 34, wherein the CD20 binding antibody is a chimeric antibody comprising the variable regions from a murine antibody fused to the constant regions of a human antibody.

45. The method of claim 44, wherein the chimeric antibody is Rituxan™

.

46. The method of claim 34, wherein the CD20 binding antibody is a humanized antibody.

48. The method of claim 41, wherein the CD20 binding antibody is Rituxan™

or hu2H7v.16 having the light and heavy chain sequence of SEQ ID NO.15 and SEQ ID NO.16, respectively.

49. The method of claim 48, wherein BR3-Fc is administered at a dosage of about 2-5 mg/kg and Rituxan is administered at a dosage of about 2.5-10 mg/kg.

50. The method of claim 34, wherein administration of the BLyS antagonist and the CD20 binding antibody produces a synergistic effect to deplete the B cells.

51. The method of claim 38, wherein the BLyS antagonist and the CD20 binding antibody is administered in conjunction with therapy using a drug selected from nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoid, prednisone, and disease-modifying antirheumatic drug (DMARD).

52. A method of depleting marginal zone or germinal center B cells in a patient suffering from a B cell neoplasm or a B-cell regulated autoimmune disorder, comprising administering to a patient in need thereof, a therapeutically effective amount of a CD20 binding antibody and of a BLyS antagonist.

54. A composition comprising a CD20 binding antibody and a BLyS antagonist.

55. An article of manufacture comprising CD20 binding antibody, a BLyS antagonist, and a label wherein the label indicates that the composition is for treating a B cell neoplasm or a B cell regulated autoimmune disorder.