ANTI-CERAMIDE ANTIBODIES

• US 20170335014A1
• Filed: 08/07/2015
• Published: 11/23/2017
• Est. Priority Date: 08/07/2014
• Status: Active Grant

• Current Assignee: Ceramide Therapeutics, Memorial Sloan-Kettering Cancer Center
• Original Assignee: Memorial Sloan-Kettering Cancer Center
• Inventors: ROTOLO, Jimmy, KOLESNICK, Richard
• Granted Patent: US 10,450,385 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• 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 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 39/00 General protective or antinoxious agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/44 against material not provided for elsewhere , e.g. haptens, metals, DNA, RNA, amino acids
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Abstract

Monoclonal antibodies directed to ceramide that inhibit apoptosis are disclosed. Humanized and scFv versions of the antibodies are also disclosed. Methods for prevention or treatment of apoptosis in a subject by administration of the anti-ceramide antibodies are disclosed.

Claims

1-26. -26. (canceled)

27. An anti-ceramide antibody or antigen-binding fragment thereof comprising a variable heavy chain (V_H) and a variable light chain (V_L), wherein

the V_H comprises a heavy chain variable region CDR1 comprising the sequence GYTFTDHTIH (SEQ ID NO:

1), a heavy chain variable region CDR2 comprising the sequence YNYPRDGSTKYNEKFKG (SEQ ID NO;

     2), and a heavy chain variable region CDR3 comprising the sequence GFITTVVPSAY (SEQ ID NO;

     3), and

the V_L comprises a light chain variable region CDR1 comprising the sequence RASKSISKYLA (SEQ ID NO;

     4), a light chain variable region CDR2 comprising the sequence SGSTLQS (SEQ ID NO;

     5), and a light chain variable region CDR3 comprising the sequence QQHNEYPWT (SEQ ID NO;

     6).

28. An anti-ceramide antibody or antigen-binding fragment thereof comprising

a heavy chain variable region sequence that is at least about 90% identical to a heavy chain variable region sequence comprising SEQ ID NO:

7; and

/or

a light chain variable region sequence that is at least about 90% identical to a light chain variable region sequence comprising SEQ ID NO;

8.

29. An anti-ceramide antibody or antigen-binding fragment thereof comprising

a heavy chain variable region sequence of QVQLQQSDAELVKPGASVKISCKVSGYTFTDHTIHWMKQRPEQGLEWIGYNYPRDGST KYNEKFKGKATLTADKSSSTAYMQLNSLTSEDSAVYFCAKGFITTVVPSAYWGQGTLV TVSA (SEQ ID NO:

48) and/or

a light chain variable region sequence of DVQITQSPSYLAASPGETITINCRASKSISKYLAWYQEKPGKTNKLLIYSGSTLQSGIPSRF SGSGSGTDFTLTISSLEPEDFAMYYCQQHNEYPWTFGGGTKLEIK (SEQ ID NO;

     8).

30. The anti-ceramide antibody or antigen-binding fragment of claim 27, wherein the antibody is selected from the group consisting of a monoclonal antibody, a chimeric antibody, a humanized antibody, a human antibody and a scFv.

31. The anti-ceramide antibody of claim 30, wherein the antibody is a scFv.

32. An anti-ceramide antibody or antigen-binding fragment thereof that binds to the same antigenic determinant as the anti-ceramide antibody or antigen-binding fragment of claim 27.

33. A method of inhibiting apoptosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the anti-ceramide antibody or antigen-binding fragment of claim 27.

34. The method of claim 33, wherein the anti-ceramide antibody is a scFv antibody.

35. The method of claim 33, wherein the apoptosis is associated with a disease selected from the group consisting of graft versus host disease, radiation disease, GI syndrome, and autoimmune disease.

36. The method of claim 35, wherein the disease is radiation disease or GI syndrome and the anti-ceramide antibody or antigen-binding fragment is administered before the subject is exposed to radiation.

37. The method of claim 35, wherein the disease is graft versus host disease and the anti-ceramide antibody or antigen-binding fragment is administered before the subject receives a transplant.

38. The method of claim 37, wherein the transplant is a bone marrow transplant.

39. The method of claim 33, wherein the anti-ceramide antibody or antigen-binding fragment is administered intravenously, intramuscularly, intraperitoneally, intracerobrospinally, subcutaneously, intrasynovially, intrathecally, orally, topically, or via inhalation.

40. A method for mitigating apoptosis in a subject with GI syndrome comprising:

administering to the subject an effective amount of the anti-ceramide antibody or antigen binding fragment of claim 27, after the subject is exposed to penetrating radiation.

41. The method of claim 40, wherein the anti-ceramide antibody is an scFv antibody.

42. The method of claim 40, wherein the anti-ceramide antibody or antigen binding fragment is administered immediately after the subject is exposed to penetrating radiation.

43. The method of claim 40, wherein the anti-ceramide antibody or antigen binding fragment is administered within 24 hours after the subject is exposed to penetrating radiation.

44. A method for inhibiting apoptosis in a subject with GvHD comprising:

administering to the subject an effective amount of the anti-ceramide antibody or antigen binding fragment of claim 27, either before the subject receives a transplant or after the subject receives a transplant prior to the onset of GvHD.

45. The method of claim 44, wherein the transplant is a bone marrow transplant.

46. The method of claim 44, wherein the anti-ceramide antibody is a scFv antibody.