Methods for the Treatment of Autoimmune Disorders Using Immunosuppressive Monoclonal Antibodies with Reduced Toxicity

• US 20080095766A1
• Filed: 06/14/2007
• Published: 04/24/2008
• Est. Priority Date: 06/14/2006
• Status: Active Grant

• Current Assignee: Provention Bio, Inc. (Sanofi )
• Original Assignee: MacroGenics, Inc.
• Inventors: Pillemer, Stanley, Bonvini, Ezio, Koenig, Scott, Wilder, Ronald, Johnson, Leslie
• Granted Patent: US 9,056,906 B2
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• 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 1/10 Laxatives
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• 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 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2809 : against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/41 : Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/71 : Decreased effector function due to an Fc-modification

Abstract

The present invention provides methods of treating, preventing, slowing the progression of, or ameliorating the symptoms of T cell mediated immunological diseases, particularly autoimmune diseases (e.g., autoimmune diabetes (i.e. type 1 diabetes or insulin-dependent diabetes mellitus (IDDM)) and multiple sclerosis) through the use of anti-human CD3 antibodies. The antibodies of the invention of the invention are preferably used in low dose dosing regimens, chronic dosing regimens or regimens that involve redosing after a certain period of time. The methods of the invention provide for administration of antibodies that specifically bind the epsilon subunit within the human CD3 complex. Such antibodies modulate the T cell receptor/alloantigen interaction and, thus, regulate the T cell mediated cytotoxicity associated with autoimmune disorders. Additionally, the methods of the invention provide for use of anti-human CD3 antibodies modified such that they exhibit reduced or eliminated effector function and T cell activation as compared to non-modified anti-human CD3 antibodies.

Claims

1. A method of treating, slowing the progression of, or ameliorating one or more symptoms of an autoimmune disorder in a patient diagnosed with said disorder, said method comprising administering to said patient a course of treatment with a therapeutically effective amount of an anti-human CD3 antibody that has at least 50% reduced binding to at least one Fcγ

R relative to an antibody with a wild type Fc domain, wherein said administration results in reduced symptoms of cytokine release relative to an equivalent administration of murine OKT3, wherein less than 9000 g/m², or the pharmacological equivalent of less than 9000 μ

g/m² of OKT3γ

1 (ala-ala) administered intravenously, is administered in said course of treatment.

3. The method of claim 1, wherein the anti-human CD3 antibody has at least 50% reduced binding to each Fcγ

R than an antibody with a wild type Fc domain.

5. The method of claim 1, wherein said antibody has at least 50% reduced binding to C1q.

7. The method of claim 1, wherein said anti-CD3 antibody is chimeric or humanized.

8. The method of claim 1, wherein said antibody is a humanized or chimerized version of OKT3, Leu-4, 500A2, CLB-T3/3, M291, YTH 12.5 or BMA030.

9. The method of claim 1, wherein said antibody is aglycosylated.

10. The method of claim 1, wherein said antibody has an Fe domain having an amino acid modification, wherein said modified Fc domain does not bind any Fcγ

R.

11. The method of claim 10, wherein said antibody is humanized OKT3γ

1 ala-ala.

12. The method of claim 10, wherein the antibody is ChAglyCD3 or visilizumab.

13. The method of claim 1, wherein said treatment comprises administration of doses of said antibody on at least 4 consecutive days.

16. The method of claim 1, wherein said treatment comprises a dosage regimen comprising doses of increasing amounts of said antibody on at least the initial 3 days of said course of treatment.

19. The method of claim 16, wherein the dose on day 1 is approximately 51 μ

g/m², the dose on day 2 is approximately 103 μ

g/m², the dose on day 3 is approximately 207 μ

g/m², the dose on day 4 is approximately 413 μ

g/m², and the dose on subsequent days is approximately 826 μ

g/m², or the pharmacological equivalent of intravenous administration of these amounts of OKT3γ

1 (ala-ala).

21. The method of claim 16, wherein the dose on day 1 is approximately 17 μ

g/m², the dose on day 2 is approximately 34.3 μ

g/m², the dose on day 3 is approximately 69 μ

g/m², the dose on day 4 is approximately 137 μ

g/m², and the dose on subsequent days is approximately 275 μ

g/m² or the pharmacological equivalent of intravenous administration of these amounts of OKT3γ

1 (ala-ala).

23. The method of claim 1, wherein said course of treatment achieves a combined T cell receptor coating and modulation of at least 50%.

25. The method of claim 1 wherein said antibody is administered intravenously in one infusion over a period of at least 18 hours.

26. The method of claim 25 in which said administration results in levels of free anti-human CD3 antibody that do not exceed 200 ng/ml.

31. The method of claim 1, wherein said autoimmune disorder is Type 1 diabetes.

32. The method of claim 1, wherein said autoimmune disorder is multiple sclerosis.

33. The method of claim 31 wherein said patient is redosed if the average daily dose of insulin has increased by 50% or more, if autoantibodies against one or more islet cell antigens are detected, if islet cell antigen specific T cells are detected, if β

-cell mass decreases by 50% or more, or if the incidence of hypoglycemic or ketoacidosis episodes increases by 1 or more incidents per day in said patient at least 2 years after initial administration of said course of treatment.

38. The method of claim 31, wherein said treatment results in an increase in the average daily dose of insulin of no more than 0.2 U/kg/day six months after said treatment, in a HA1c of less than 7.5% one year after said treatment, or in a C-peptide response to MMTT twelve months after said treatment that is at least 90% of the C-peptide response to MMTT in said patient before said treatment.

41. The method of claim 32, wherein said treatment results in an increase in the total number or total area of lesions as determined by MRI by no more than 10% twelve months after treatment or wherein said treatment results in no increase in the total number or total area of lesions relative to pre-treatment levels as determined by MRI at twelve months after treatment.

46. The method of claim 1, in which said administration does not result in EBV-induced lymphoproliferative diseases or lymphocyte counts less than 1000 lymphocytes/μ

l serum.

52. The method of claim 1, wherein said autoimmune disorder is psoriasis, rheumatoid arthritis, lupus, inflammatory bowel disease (IBD), ulcerative colitis, Crohn'"'"'s disease, multiple sclerosis, effects from organ transplantation, or graft vs. host disease (GVHD).

2. A method of preventing or delaying the onset of an autoimmune disorder in a patient predisposed thereto but not diagnosed with said disorder, said method comprising administering to said patient a therapeutically effective amount of an anti-human CD3 antibody that has at least 50% reduced binding to at least one Fcγ

R relative to an antibody with a wild type Fe domain, wherein said administration results in reduced symptoms of cytokine release relative to an equivalent administration of murine OKT3, wherein less than 9000 μ

g/m², or the pharmacological equivalent of less than 9000 μ

g/m² of OKT3γ

1 (ala-ala) administered intravenously, is administered in said course of treatment.

4. (canceled)

6. (canceled)

14-15. -15. (canceled)

17-18. -18. (canceled)

20. (canceled)

22. (canceled)

24. (canceled)

27-30. -30. (canceled)

34-37. -37. (canceled)

39-40. -40. (canceled)

42-45. -45. (canceled)

47. A method of treating, slowing the progression of, or ameliorating one or more symptoms of an autoimmune disorder in a patient diagnosed with said autoimmune disorder, said method comprising chronically administering to said patient a therapeutically effective amount of an anti-human CD3 antibody that has at least 50% reduced binding to at least one Fcγ

R than an antibody with a wild type Fc domain, wherein said administration results in reduced symptoms of cytokine release relative to an equivalent administration of murine OKT3.

49. The method of claim 47, wherein said autoimmune disorder is Type 1 diabetes.

50. The method of claim 47, wherein said autoimmune disorder is multiple sclerosis.

51. The method of claim 47, wherein said patient had been administered a 6 to 20 day course of treatment with said anti-human CD3 antibodies prior to said chronic administration.

48. A method of preventing or delaying the onset of an autoimmune disorder in a patient predisposed thereto but not diagnosed with said autoimmune disorder, said method comprising chronically administering to said a therapeutically effective amount of an anti-human CD3 antibody that has at least 50% reduced binding to at least one Fcγ

R than an antibody with a wild type Fc domain, wherein said administration results in reduced symptoms of cytokine release relative to an equivalent administration of murine OKT3.

53. A method of treating, slowing the progression of, or ameliorating one or more symptoms of multiple sclerosis in a patient diagnosed with multiple sclerosis, said method comprising administering to said patient a course of treatment with a therapeutically effective amount of an anti-human CD3 antibody that has at least 50% reduced binding to at least one Fcγ

R relative to an antibody with a wild type Fc domain, wherein said administration results in reduced symptoms of cytokine release relative to an equivalent administration of murine OKT3.

54. A method of preventing or delaying the onset of multiple sclerosis in a patient predisposed thereto but not diagnosed with multiple sclerosis, said method comprising administering to said patient a therapeutically effective amount of an anti-human CD3 antibody that has at least 50% reduced binding to at least one Fcγ

R relative to an antibody with a wild type Fc domain, wherein said administration results in reduced symptoms of cytokine release relative to an equivalent administration of murine OKT3.