Use of anti-CGRP antibodies and antibody fragments to treat diarrhea in subjects with diseases or treatments that result in elevated CGRP levels

Patent metadata

Field	Value
Publication number	US-9855332-B2
Application number	US-201213476104-A
Country	US
Kind code	B2
Filing date	May 21, 2012
Priority date	May 20, 2011
Publication date	Jan 2, 2018
Grant date	Jan 2, 2018

Abstract

The present invention is directed to methods for treating diarrhea, both chronic or acute forms, by the administration of a therapeutically or prophylactically effective amount of antibodies and fragments thereof having binding specificity for CGRP. In particular the methods prevent or reduce diarrhea in conditions or treatments resulting in elevated CGRP levels, e.g., in the GI tract (colon) that are associated with diarrhea and/or improper electrolyte and fluid excretion from the bowel or urinary system. More specifically, this invention relates to treatments using the anti-CGRP antibodies and fragments described herein, and binding fragments thereof.

First claim

What is claimed is:

1. A method of inhibiting, or treating diarrhea in a subject with diarrhea and comprising elevated levels of CGRP comprising administering an effective amount of an anti-CGRP antibody or anti-CGRP antibody fragment.

2. The method of claim 1 , comprising the administration of an intact anti-CGRP antibody.

3. The method of claim 2 , wherein said antibody is humanized, or chimeric.

4. The method of claim 1 , comprising the administration of an anti-CGRP antibody fragment.

5. The method of claim 4 , wherein said antibody fragment is an scFv, a camelbody, a nanobody, an IgNAR, a Fab, a Fab′, or a F(ab′) 2 fragment.

6. The method of claim 1 , wherein the anti-CGRP antibody or anti-CGRP antibody fragment is humanized.

7. The method of claim 1 , wherein the anti-CGRP antibody comprises human constant regions.

8. The method of claim 7 , wherein the constant regions are selected from the group consisting of an IgG1, IgG2, IgG3 and IgG4 constant regions.

9. The method of claim 8 , wherein the anti-CGRP antibody comprises IgG1 constant regions.

10. The method of claim 1 , wherein the anti-CGRP antibody or anti-CGRP antibody fragment is non-glycosylated.

11. The method of claim 1 wherein the anti-CGRP antibody or antibody fragment binds to CGRP with an off-rate (K off ) of less than or equal to 10 −4 S −1 , 5×10 −5 S −1 , 10 −5 S −1 , 5×10 −6 S −1 , 10 −6 S −1 , 5×10 −7 S −1 , or 10 −7 S −1 .

12. The method of claim 1 wherein the antibody or antibody fragment is administered intramuscularly, subcutaneously, intravenously, rectally, by infusion, orally, transdermally or via inhalation.

13. The method of claim 1 wherein the antibody or antibody fragment is administered intravenously.

14. The method of claim 1 , wherein the anti-CGRP antibody or antibody fragment is administered as a monotherapy.

15. The method of claim 1 , wherein the antibody or antibody fragment is administered with another anti-diarrhea treatment agent.

16. The method of claim 15 , wherein the other agent is an anti-motility agent selected from the group consisting of loperamide, a bismuth compound, codeine, a zinc compound, a bile acid sequestrant, an electrolyte solution or a probiotic.

17. The method of claim 1 , wherein the antibody or antibody fragment is non-glycosylated or lacks N-glycosylation or if glycosylated only contains only mannose residues and/or contains an Fc region that has been modified to alter effector function, half-life, proteolysis, and/or glycosylation.

18. The method of claim 1 , wherein the condition associated with diarrhea is a bacterial, parasitic or viral induced diarrhea.

19. The method of claim 18 , wherein said virus comprises a calicivirus, rotavirus, RSV, HIV, norvovirus, adenovirus, or astrovirus.

20. A method of inhibiting, preventing or treating diarrhea in a subject comprising elevated levels of CGRP comprising administering an effective amount of an anti-CGRP antibody or anti-CGRP antibody fragment, wherein the anti-CGRP antibody or antibody fragment comprises the variable light (V L ) CDR1, CDR2, and CDR3 of SEQ ID NOs:55, 56 and 57, respectively, and the variable heavy (V H ) CDR1, CDR2, and CDR3 of SEQ ID NOs:58, 59 and 60, respectively.

21. The method of claim 20 , wherein the anti-CGRP antibody or anti-CGRP antibody fragment comprises a variable light (V L ) chain polypeptide that possesses at least 90% sequence identity to the polypeptide of SEQ ID NO:31, 41 or 51.

22. The method of claim 20 , wherein the anti-CGRP antibody or anti-CGRP antibody fragment comprises a variable heavy (V H ) polypeptide that possesses at least 90% sequence identity to the polypeptide of SEQ ID NO:33, 43 or 53.

23. The method of claim 20 , wherein the anti-CGRP antibody or anti-CGRP antibody fragment comprises a variable light (V L ) chain polypeptide that possesses at least 95% sequence identity to the polypeptide of SEQ ID NO:31, 41 or 51.

24. The method of claim 20 , wherein the anti-CGRP antibody or anti-CGRP antibody fragment comprises a variable heavy (V H ) polypeptide that possesses at least 95% sequence identity to the polypeptide of SEQ ID NO:33, 43 or 53.

25. The method of claim 20 , wherein the anti-CGRP antibody or anti-CGRP antibody fragment comprises the variable light (V L ) chain polypeptide of SEQ ID NO:31, 41 or 51.

26. The method of claim 20 , wherein the anti-CGRP antibody or anti-CGRP antibody fragment comprises the variable heavy (V H ) polypeptide of SEQ ID NO:33, 43 or 53.

27. The method of claim 20 , wherein the anti-CGRP antibody or anti-CGRP antibody fragment comprises the variable light (V L ) chain polypeptide of SEQ ID NO:31, 41 or 51 and the variable heavy (V H ) polypeptide of SEQ ID NO:33, 43 or 53.

28. The method of claim 20 , wherein the anti-CGRP antibody or anti-CGRP antibody fragment comprises the variable light (V L ) chain polypeptide of SEQ ID NO:51 and the variable heavy (V H ) polypeptide of SEQ ID NO:53.

29. The method of claim 20 , wherein the anti-CGRP antibody or anti-CGRP antibody fragment comprises the light chain polypeptide of SEQ ID NO:32, 42 or 52 and the heavy chain polypeptide of SEQ ID NO:34, 44 or 54.

30. The method of claim 20 , wherein the anti-CGRP antibody or anti-CGRP antibody fragment comprises the light chain polypeptide of SEQ ID NO: 52 and the heavy chain polypeptide of SEQ ID NO: 54.

Assignees

• Russo Andrew F
• Kaiser Eric A
• Recober Ana
• Kuburas Adisa
• Raddant Ann C
• Kovacevich Brian Robert
• Latham John A
• Smith Jeffrey T L
• Garcia-Martinez Leon F
• Alderbio Holdings Llc

Inventors

• Russo Andrew F
• Kaiser Eric A
• Recober Ana
• Kuburas Adisa
• Raddant Ann C
• Kovacevich Brian Robert
• Latham John A
• Smith Jeffrey T L
• Garcia-Martinez Leon F

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P31/04

  Antibacterial agents · CPC title