# US 2014/0154268 A1 · Alpha5-beta1 antibodies and their uses

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- Number: US 2014/0154268 A1
- Document ID: US20140154268A1
- Status: Published application
- Kind: A1
- Application number: 13/772,992
- Filed: 2013-02-21
- Published: 2014-06-05
- Earliest claimed: 2008-02-05
- Assignees: Pfizer Inc.; Bristol-Myers Squibb Company
- Applicants: Pfizer Inc.; Bristol-Myers Squibb Company
- Inventors: STEVEN LEE BENDER; GERALD FRIES CASPERSON; DANA DAN HU-LOWE; XIN JIANG; GANG LI; MICHAEL AIDAN NORTH; JIANYING WANG; GRANT WICKMAN; PETER BRAMS; HAICHUN HUANG; BRIGITTE DEVAUX; HAIBIN CHEN; DAWN M. TANAMACHI; KRISTOPHER TOY; LAN YANG; TIM W. SPROUL; MARK YAMANAKA
- Web page: https://patentgrep.com/patent/US20140154268A1

## CPC

- C07K 16/2842: {against integrin beta1-subunit-containing molecules, e.g. CD29, CD49}
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 13/08: of the prostate
- A61P 13/10: of the bladder
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 19/00: Drugs for skeletal disorders
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/02: Ophthalmic agents
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61K 2039/505: {comprising antibodies}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/567: Framework region [FR]
- C07K 2317/72: Increased effector function due to an Fc-modification
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

The present disclosure provides isolated monoclonal antibodies, particularly human monoclonal antibodies, or antigen binding portions thereof, that specifically bind to integrin α5β1 with high affinity. Nucleic acid molecules encoding the antibodies of the disclosure, expression vectors, host cells and methods for expressing the antibodies of the disclosure are also provided. Immunoconjugates, bispecific molecules and pharmaceutical compositions comprising the antibodies or antigen binding portions thereof are also provided. The disclosure also provides methods for treating various cancers using the anti-α5β1 antibodies or antigen binding portions thereof described herein.

## Claims

### Claim at position 1

1-10. (canceled)

### Claim 11

An isolated monoclonal antibody, or an antigen-binding portion thereof, that:
(a) binds to human integrin α5β1 with a KD of 1×10−7 M or less; and
(b) is capable of inducing antibody dependent cellular cytotoxicity (ADCC).

### Claim 12 (depends on 11)

The antibody of claim 11, which is a full-length human antibody of subclass IgG1.

### Claim 13 (depends on 11)

The antibody or antigen-binding portion thereof of claim 11, wherein said antibody or antigen-binding portion binds to human integrin α5β1 with a KD of 5×10−8 M or less.

### Claim 14 (depends on 12)

The antibody of claim 12, wherein at least one amino acid in the Fc region of said antibody is mutated, and further wherein said antibody exhibits greater ADCC than an identical antibody wherein said at least one amino acid is not mutated.

### Claim 15 (depends on 14)

The antibody of claim 14, wherein the at least one mutation occurs at amino acid position serine 247, alanine 338, or isoleucine 340.

### Claim 16 (depends on 15)

The antibody of claim 15, where the at least one mutation is selected from the group consisting of serine 247 to aspartic acid (S247D), alanine 338 to leucine (A338L), and isoleucine 340 to glutamic acid (I340E).

### Claim 17

An isolated human full-length IgG1 antibody having at least one Fc region amino acid mutation, exhibiting greater antibody dependent cellular cytotoxicity (ADCC) than an identical antibody without the at least one Fc region amino acid mutation and capable of binding to human integrin α5β1 with a KD of 1×10−7 M or less.

### Claim 18 (depends on 17)

The antibody of claim 17, wherein said antibody binds to human integrin α5β1 with a KD of 5×10−8 M or less.

### Claim 19

An isolated monoclonal antibody or antigen-binding portion thereof that binds to human integrin α5β1 with a KD of 1×10−7 M or less and comprises a heavy chain variable region that is at least 90% identical to the amino acid sequence set forth in SEQ ID NO:7.

### Claim 20 (depends on 19)

The antibody or antigen-binding portion thereof of claim 19 further comprising a light chain variable region that is at least 90% identical to the amino acid sequence set forth in SEQ ID NO:8.

### Claim 21 (depends on 11)

A composition comprising the antibody or antigen-binding portion of claim 11, and a pharmaceutically acceptable carrier.

### Claim 22 (depends on 11)

An isolated nucleic acid molecule encoding the heavy and/or light chain of the antibody, or antigen-binding portions thereof of claim 11.

### Claim 23 (depends on 22)

An expression vector comprising the nucleic acid molecule of claim 22.

### Claim 24 (depends on 23)

A host cell comprising the expression vector of claim 23.

### Claim 25 (depends on 24)

A method for preparing an anti-α5β1 antibody or antigen-binding portion thereof, comprising expressing the antibody or antigen-binding portion in the host cell of claim 24.

### Claim 26 (depends on 11)

A method of inhibiting growth of tumor cells expressing integrin α5β1, comprising contacting the cells with the antibody, or antigen-binding portion thereof, of claim 11 in an amount effective to inhibit growth of the tumor cells.