# US 11,027,018 B2 · Use of anti-CGRP antibodies and antibody fragments to treat diarrhea in subjects with diseases or treatments that result in elevated CGRP levels

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- Number: US 11,027,018 B2
- Document ID: US11027018B2
- Status: Granted
- Kind: B2
- Application number: 16/274,985
- Filed: 2019-02-13
- Published: 2019-08-08
- Granted: 2021-06-08
- Earliest claimed: 2011-05-20
- Assignees: University of Iowa Research Foundation; H. Lundbeck A/S
- Applicants: Alderbio Holdings LLC
- Inventors: Andrew F. Russo; Eric A. Kaiser; Ana Recober; Adisa Kuburas; Ann C. Raddant; Brian R. Kovacevich; John Latham; Jeffrey T. L. Smith; Leon F. Garcia-Martinez
- Web page: https://patentgrep.com/patent/US11027018B2

## CPC

- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/12: Antidiarrhoeals
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 3/12: for electrolyte homeostasis
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 33/00: Antiparasitic agents
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/26: against hormones {; against hormone releasing or inhibiting factors}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## 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.

## Claims

### Claim 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 (VL) 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 (VH) 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.

### Claim 2 (depends on 1)

The method of claim 1, wherein the anti-CGRP antibody or anti-CGRP antibody fragment comprises a variable light (VL) chain polypeptide that possesses at least 90% sequence identity to the polypeptide of SEQ ID NO: 21.

### Claim 3 (depends on 1)

The method of claim 1, wherein the anti-CGRP antibody or anti-CGRP antibody fragment comprises a variable light (VL) chain polypeptide that possesses at least 95% sequence identity to the polypeptide of SEQ ID NO: 21.

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 1)

The method of claim 1, wherein the anti-CGRP antibody or anti-CGRP antibody fragment comprises a variable heavy (VH) polypeptide that possesses at least 90% sequence identity to the polypeptide of SEQ ID NO: 23.

### Claim 6 (depends on 2)

The method of claim 2, wherein the anti-CGRP antibody or anti-CGRP antibody fragment comprises a variable heavy (VH) polypeptide that possesses at least 95% sequence identity to the polypeptide of SEQ ID NO: 23.

### Claim 7 (depends on 2)

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

### Claim 8 (depends on 1)

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

### Claim 9 (depends on 1)

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

### Claim 10 (depends on 1)

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

### Claim 11 (depends on 1)

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

### Claim 12 (depends on 1)

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.

### Claim 13 (depends on 12)

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.

### Claim 14 (depends on 1)

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

### Claim 15 (depends on 1)

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.

### Claim 16 (depends on 1)

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.

### Claim 17 (depends on 1)

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

### Claim 18 (depends on 1)

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 (VH) chain polypeptide having the sequence of SEQ ID NO: 24.