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-11027018-B2
Application number	US-201916274985-A
Country	US
Kind code	B2
Filing date	Feb 13, 2019
Priority date	May 20, 2011
Publication date	Jun 8, 2021
Grant date	Jun 8, 2021

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 a variable light (V L ) chain comprising the complementarity determining region (“CDR”) 1 sequence of SEQ ID NO: 25, the CDR2 sequence of SEQ ID NO: 26, and the CDR3 sequence of SEQ ID NO: 27, and a variable heavy (V H ) chain comprising the CDR1 sequence of SEQ ID NO: 28, the CDR2 sequence of SEQ ID NO: 29, and the CDR3 sequence of SEQ ID NO: 30.

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: 21.

3. 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: 21.

4. The method of claim 1 , wherein the anti-CGRP antibody or anti-CGRP antibody fragment comprises a variable light (V L ) chain polypeptide of SEQ ID NO: 21.

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 90% sequence identity to the polypeptide of SEQ ID NO: 23.

6. The method of claim 2 , 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: 23.

7. The method of claim 2 , wherein the anti-CGRP antibody or anti-CGRP antibody fragment comprises a variable heavy (V H ) polypeptide of SEQ ID NO: 23.

8. The method of claim 1 , wherein the anti-CGRP antibody or anti-CGRP antibody fragment comprises a variable light (V L ) chain polypeptide having at least 90% sequence identity to the polypeptide of SEQ ID NO: 21, and a variable heavy (V H ) chain polypeptide having at least 90% sequence identity to the polypeptide of SEQ ID NO: 23.

9. The method of claim 1 , wherein the anti-CGRP antibody or anti-CGRP antibody fragment comprises a variable light (V L ) chain polypeptide having at least 95% sequence identity to the polypeptide of SEQ ID NO: 21 and a variable heavy (V H ) chain polypeptide having at least 95% sequence identity to the polypeptide of SEQ ID NO: 23.

10. The method of claim 1 , wherein the anti-CGRP antibody or anti-CGRP antibody fragment comprises a variable light (V L ) chain polypeptide having a polypeptide sequence of SEQ ID NO: 21, and a variable heavy (V H ) chain polypeptide having a polypeptide sequence of SEQ ID NO: 23.

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

12. The method of claim 1 , 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.

13. The method of claim 12 , 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 selected from rotavirus, RSV, HIV, norvovirus, adenovirus, and astrovirus.

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

15. The method of claim 1 , 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.

16. 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.

17. The method of claim 1 , wherein said anti-CGRP antibody or antibody fragment lacks glycosylation or comprises only mannose residues.

18. The method of claim 1 , wherein the anti-CGRP antibody or anti-CGRP antibody fragment is an anti-CGRP antibody that comprises a light chain polypeptide having the sequence of SEQ ID NO: 22 and a variable heavy (V H ) chain polypeptide having the sequence of SEQ ID NO: 24.

Assignees

• Alderbio Holdings Llc
• The Univ Of Iowa Research Foundation
• H Lundbeck As

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

• A61K2039/505

  comprising antibodies · CPC title