METHODS FOR TREATING AND PREVENTING GI SYNDROME AND GRAFT VERSUS HOST DISEASE

• US 20100239572A1
• Filed: 05/06/2008
• Published: 09/23/2010
• Est. Priority Date: 05/06/2007
• Status: Active Grant

• Current Assignee: Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center), Board of Regents of the University of Texas System (University of Texas System), University of Texas System
• Original Assignee: Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center)
• Inventors: Kolesnick, Richard, Rotolo, Jimmy Andrew, Arap, Wadih, Pasqualini, Renata
• Granted Patent: US 8,562,993 B2
• Time in Patent Office: Days
• US Class Current: 424/133.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 Immunomodulators
• 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: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C07K 16/44 against material not provided for elsewhere , e.g. haptens, metals, DNA, RNA, amino acids

Abstract

We have discovered that administering anti-ceramide antibody treats and prevents an array of diseases mediated by cytolytic T lymphocyte (CTLs)-induced killing and by damage to endothelial microvasculture, including radiation-induced GI syndrome, Graft vs. Host diseases, inflammatory diseases and autoimmune diseases. We have also discovered new anti-ceramide monoclonal antibodies, that have therapeutic use preferably in humanized form to treat or prevent these diseases.

Claims

1. A method for preventing or treating a disease selected from the group consisting of graft versus host disease, radiation disease, GI syndrome and autoimmune disease in an animal, comprising administering a therapeutically effective amount of an anti-ceramide antibody or a biologically active fragment thereof.

2. The method of claim 1, wherein the antibody is humanized.

3. The method of claim 2, wherein the antibody is a monoclonal antibody.

4. The method of claim 3, wherein the monoclonal antibody is 2A2 IgM.

13. The method of claim 1, wherein the disease is radiation disease or GI syndrome and the antibody is administered before the animal is exposed to radiation.

15. The method of claim 1, wherein the disease is graft v. host disease and the antibody is administered before the animal receives a bone marrow transplant.

5. The monoclonal antibody 2A2 IgM or a biologically active fragment thereof.

7. A pharmaceutical composition comprising the monoclonal antibody 2A2 IgM or a biologically active fragment thereof.

8. The pharmaceutical composition of claim 7, wherein the antibody is humanized.

9. The pharmaceutical composition of claim 7, further comprising a statin.

10. The composition of claim 7, further comprising imipramine.

11. A method for preventing or treating a disease selected from the group consisting of graft versus host disease, radiation disease, GI syndrome and autoimmune disease in an animal, comprising administering a therapeutically effective amount of imipramine.

12. A method for treating or preventing a disease selected from the group consisting of graft versus host disease, radiation disease, GI syndrome and autoimmune disease in an animal, comprising administering a therapeutically effective amount of an antisense nucleic acid from 8-50 nucleotides in length selected from the group consisting of antisense nucleic acids that are sufficiently complementary to the human gene identified as SEQ ID NO:

7 or the cDNA identified as SEQ ID NO;

2 encoding ASMase to hybridize to it thereby reducing its expression, antisense nucleic acids sufficiently complementary to the human gene identified as SEQ ID NO;

8 or the cDNA identified as SEQ ID NO;

4 encoding Bax to hybridize to it thereby reducing its expression, and antisense nucleic acids sufficiently complementary to the human gene identified as SEQ ID NO;

9 or the cDNA identified as SEQ ID NO;

6 encoding Bak to hybridize to it thereby reducing its expression.

6. The 2A2 IgM of claim 12, wherein the antibody is humanized.

14. The method of claim 12, wherein the disease is radiation disease or GI syndrome and the antibody is administered before the animal is exposed to radiation.

16. The method of claim 12, wherein the disease is graft v. host disease and the antibody is administered before the animal receives a bone marrow transplant.

17. A monoclonal antibody or a biologically active fragment or variant thereof selected from the group comprising 1H4, 15D9 and 5H9 mouse monoclonal antibodies.

18. The monoclonal antibodies of claim 17, wherein the antibodies are humanized.

19. Monoclonal antibodies that cross-react with ceramide, wherein spleen cells used to make a hybridoma that secretes the monoclonal antibodies are obtained from an animal immunized with whole cells.

20. The monoclonal antibodies of claim 19, wherein the whole cells are Kaposi Sarcoma (KS) cells or other cells that recapitulate activated endothelium.