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-10765746-B2
Application number	US-201715818000-A
Country	US
Kind code	B2
Filing date	Nov 20, 2017
Priority date	May 20, 2011
Publication date	Sep 8, 2020
Grant date	Sep 8, 2020

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, preventing or treating diarrhea in a subject comprising elevated levels of CGRP, wherein said elevated CGRP levels are associated with an acute condition 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.

2. The method of claim 1 , 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.

3. The method of claim 1 , 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.

4. The method of claim 1 , 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.

5. The method of claim 1 , 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.

6. The method of claim 1 , 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.

7. The method of claim 1 , 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.

8. The method of claim 1 , 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.

9. The method of claim 1 , 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.

10. The method of claim 1 , 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.

11. The method of claim 1 , 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.

12. The method of claim 1 , wherein the acute condition resulting in diarrhea is food poisoning.

13. The method of claim 1 , wherein said anti-CGRP antibody or antibody fragment is entirely aglycosylated or lacks N-glycosylation or comprises only mannose residues.

14. A method of inhibiting, preventing or treating diarrhea in a subject comprising elevated levels of CGRP, wherein said elevated CGRP levels are associated with a chronic condition 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.

15. The method of claim 14 , 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.

16. The method of claim 14 , 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.

17. The method of claim 14 , 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.

18. The method of claim 14 , 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.

19. The method of claim 14 , 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.

20. The method of claim 14 , 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.

21. The method of claim 14 , 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.

22. The method of claim 14 , 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.

23. The method of claim 14 , 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.

24. The method of claim 14 , 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.

25. The method of claim 14 , wherein the chronic condition associated with diarrhea is
(i) a functional bowel disorder selected from the group consisting of gastro-esophageal reflux, dyspepsia, irritable bowel syndrome, functional abdominal pain syndrome, bile acid malabsorption, diverticulitis, or an inflammatory bowel disease selected from the group consisting of Crohn's disease, ileitis, collagenous colitis, lymphocytic colitis, and ulcerative colitis; or
(ii) a cancer and the diarrhea is caused by the cancer or a cancer treatment regimen.

26. The method of claim 14 , wherein said anti-CGRP antibody or antibody fragment is entirely aglycosylated or lacks N-glycosylation or comprises only mannose residues.

27. The method of claim 1 or 14 , wherein the diarrhea comprises osmotic diarrhea, secretory diarrhea, motility diarrhea, exudative diarrhea, and/or inflammatory diarrhea.

28. The method of claim 1 or 14 , wherein the chronic or acute condition is selected from functional bowel disorder, irritable bowel syndrome, coeliac disease, pancreatic disease, pancreatitis, type 1 or type 2 diabetes, cystic fibrosis, Crohn's disease, diabetic neuropathy, menstruation, hyperthyroidism, hormone imbalance, enteritis, an inflammatory bowel disease, microscopic colitis, ischemic bowel disease, ulcerative colitis, mucositis, or tuberculosis or the chronic or acute condition associated with diarrhea is caused by a bacterial, parasitic or viral infection.

29. The method of claim 28 , wherein the condition resulting in diarrhea is caused by:
(i) a parasite selected from Entaamoeba histolytica, Giardia, or another protozoan;
(ii) a bacterium selected from E coli, Shigella, Entaamoeba histolytica, Salmonella, Campylobacter , and Clostridium difficile ; or
(iii) a virus

Assignees

• Alderbio Holdings Llc
• The Univ Of Iowa Research Foundation

Inventors

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

Classifications

• A61K31/7088

  Compounds having three or more nucleosides or nucleotides · CPC title

• A61K38/16

  Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof {(enzyme inhibitors A61K38/005)} · CPC title

• A61K48/00

  Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy · CPC title

• A61K39/395 Primary

  Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum · CPC title

• A61P29/00

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