# US 8,784,808 B2 · FcγRIIB specific antibodies and methods of use thereof

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- Number: US 8,784,808 B2
- Document ID: US8784808B2
- Status: Granted
- Kind: B2
- Application number: 13/367,626
- Filed: 2012-02-07
- Published: 2012-06-07
- Granted: 2014-07-22
- Earliest claimed: 2004-05-10
- Assignees: MacroGenics, Inc.
- Applicants: Leslie S. Johnson; Ling Huang
- Inventors: Leslie S. Johnson; Ling Huang
- Web page: https://patentgrep.com/patent/US8784808B2

## CPC

- C07K 16/283: {against Fc-receptors, e.g. CD16, CD32, CD64 (CD23 C07K16/2851)}
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- 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 invention relates to antibodies or fragments thereof that bind FcγRIIB with greater affinity than said antibodies or fragments binds FcγRIIA. The invention encompasses the use of such antibodies or fragments for the treatment of diseases related to loss of balance of Fc receptor mediated signaling, such as cancer, autoimmune diseases, inflammatory diseases or IgE-mediated allergic disorders. The present invention also encompasses the use of such antibodies and fragments in combination with other cancer therapies, methods of enhancing the therapeutic effect of therapeutic antibodies, and methods of enhancing efficacy of vaccine compositions.

## Claims

### Claim 1

A method of treating cancer in a patient having a cancer characterized by a cancer antigen, said method comprising administering to said patient a therapeutically effective amount of:
I. a humanized antibody or an antigen-binding fragment thereof that specifically binds to the extracellular domain of native human FcγRIIB with a greater affinity than said antibody binds to the extracellular domain of native human FcγRIIA, wherein said humanized antibody or antigen-binding fragment thereof comprises a human framework region and:
(A)
(1) a polypeptide comprising the amino acid sequence of SEQ ID NO. 1 (CDR1 of the heavy chain of humanized antibody 2B6), SEQ ID NO. 2 (CDR2 of the heavy chain of humanized antibody 2B6), and SEQ ID NO. 3 (CDR3 of the heavy chain of humanized antibody 2B6), and
(2) a polypeptide comprising the amino acid sequence of SEQ ID NO. 8 (CDR1 of the light chain of humanized antibody 2B6), SEQ ID NO. 11 (CDR2 of the light chain of humanized antibody 2B6), and SEQ ID NO. 12 (CDR3 of the light chain of humanized antibody 2B6); or
(B)
(1) a polypeptide comprising the amino acid sequence of SEQ ID NO. 29 (CDR1 of the heavy chain of humanized antibody 3H7), SEQ ID NO. 30 (CDR2 of the heavy chain of humanized antibody 3H7), and SEQ ID NO. 31 (CDR3 of the heavy chain of humanized antibody 3H7), and
(2) a polypeptide comprising the amino acid sequence of SEQ ID NO. 38 (CDR1 of the light chain of humanized antibody 3H7), SEQ ID NO. 39 (CDR2 of the light chain of humanized antibody 3H7), and SEQ ID NO. 40 (CDR3 of the light chain of humanized antibody 3H7);
and in combination with
II. an antibody that specifically binds said cancer antigen and is cytotoxic.

### Claim 2 (depends on 1)

The method of claim 1, wherein said humanized antibody or antigen-binding fragment thereof comprises said polypeptide (A)(1) and (A)(2).

### Claim 3 (depends on 1)

The method of claim 1, wherein said humanized antibody or antigen-binding fragment thereof comprises said polypeptide (B)(1) and (B)(2).

### Claim 4 (depends on 1)

The method of claim 1, wherein said antigen-binding fragment comprises an F(ab′)2 fragment or a F(ab) fragment of said humanized antibody.

### Claim 5 (depends on 1)

The method of claim 1, wherein said polypeptide (A)(1) and (A)(2) are covalently bonded to one another, or said polypeptide (B)(1) and (B)(2) are covalently bonded to one another.

### Claim 6 (depends on 1)

The method of claim 1, wherein said cancer is breast, ovarian, prostate, cervical, B-cell, or pancreatic cancer.

### Claim 7 (depends on 1)

The method of claim 1, wherein said cytotoxic antibody is trastuzumab, rituximab, an anti-CD14 antibody, edrecolomab, cetuximab, a humanized anti-αVβ3 integrin antibody, a humanized anti-CD52 IgG1, epratuzumab, or a murine anti-CD20 antibody.

### Claim 8 (depends on 1)

The method of claim 1, wherein said cancer antigen is MAGE-1, MAGE-3, BAGE, GAGE-1, GAGE-2, N-acetylglucosaminyltransferase, p15, beta-catenin, MUM-1, CD20, CDK4, HER-2/neu, human papillomavirus-E6, human papillomavirus-E7, or MUC-1.

### Claim 9 (depends on 1)

The method of claim 1, wherein said cancer antigen is a breast, ovarian, prostate, cervical, B-cell or pancreatic carcinoma antigen.

### Claim 10 (depends on 1)

The method of claim 1, further comprising the administration of one or more additional cancer therapies.

### Claim 11 (depends on 10)

The method of claim 10, wherein said additional cancer therapy is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, or surgery.

### Claim 12 (depends on 1)

The method of claim 1, wherein said patient is human.

### Claim 13

A method of treating cancer in a patient having a cancer characterized by a cancer antigen, said method comprising administering to said patient a therapeutically effective amount of a humanized antibody or an antigen-binding fragment thereof that specifically binds to the extracellular domain of native human FcγRIIB with a greater affinity than said antibody binds to the extracellular domain of native human FcγRIIA, wherein said humanized antibody or said antigen-binding fragment thereof possesses CDR1, CDR2 and CDR3 from an antibody heavy chain, and CDR1, CDR2 and CDR3 from an antibody light chain, and wherein said humanized antibody or fragment thereof comprises:
(1) a polypeptide comprising the amino acid sequence of SEQ ID NO. 1 (CDR1 of the heavy chain of humanized antibody 2B6), SEQ ID NO. 2 (CDR2 of the heavy chain of humanized antibody 2B6), and SEQ ID NO. 3 (CDR3 of the heavy chain of humanized antibody 2B6); or
(2) a polypeptide comprising the amino acid sequence of SEQ ID NO. 8 (CDR1 of the light chain of humanized antibody 2B6), SEQ ID NO. 11 (CDR2 of the light chain of humanized antibody 2B6), and SEQ ID NO. 12 (CDR3 of the light chain of humanized antibody 2B6); or
(3) a polypeptide comprising the amino acid sequence of SEQ ID NO. 29 (CDR1 of the heavy chain of humanized antibody 3H7), SEQ ID NO. 30 (CDR2 of the heavy chain of humanized antibody 3H7), and SEQ ID NO. 31 (CDR3 of the heavy chain of humanized antibody 3H7); or
(4) a polypeptide comprising the amino acid sequence of SEQ ID NO. 38 (CDR1 of the light chain of humanized antibody 3H7), SEQ ID NO. 39 (CDR2 of the light chain of humanized antibody 3H7), and SEQ ID NO. 40 (CDR3 of the light chain of humanized antibody 3H7);
and wherein the administered antibody reduces the population of cancer cells expressing FcγRIIB.

### Claim 14 (depends on 13)

The method of claim 13, wherein said humanized antibody or antigen-binding fragment thereof comprises said polypeptides (1) and (2).

### Claim 15 (depends on 13)

The method of claim 13, wherein said humanized antibody or antigen-binding fragment thereof comprises said polypeptides (3) and (4).

### Claim 16 (depends on 13)

The method of claim 13, wherein said antigen-binding fragment comprises an F(ab′)2 fragment or a F(ab) fragment of said humanized antibody.

### Claim 17 (depends on 14)

The method of claim 14, wherein said polypeptides (1) and (2) are covalently bonded to one another.

### Claim 18 (depends on 15)

The method of claim 15, wherein said polypeptides (3) and (4) are covalently bonded to one another.

### Claim 19 (depends on 13)

The method of claim 13, wherein said cancer is breast, ovarian, prostate, cervical, B-cell, or pancreatic cancer.

### Claim 20 (depends on 13)

The method of claim 13, comprising the further step of administering in combination with said humanized antibody or antigen-binding fragment thereof a cytotoxic antibody that specifically binds said cancer antigen, wherein said cytotoxic antibody is trastuzumab, rituximab, an anti-CD14 antibody, edrecolomab, cetuximab, a humanized anti-αVβ3 integrin antibody, a humanized anti-CD52 IgG1, epratuzumab, or a murine anti-CD20 antibody.

### Claim 21 (depends on 13)

The method of claim 13, wherein said cancer antigen is a breast, ovarian, prostate, cervical, B-cell or pancreatic carcinoma antigen.

### Claim 22 (depends on 13)

The method of claim 13, further comprising the administration of one or more additional cancer therapies.

### Claim 23 (depends on 22)

The method of claim 22, wherein said additional cancer therapy is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, or surgery.

### Claim 24 (depends on 13)

The method of claim 13, wherein said humanized antibody or antigen-binding fragment thereof has the binding characteristics of an antibody produced from a hybridoma cell line having ATCC accession number PTA-4591.

### Claim 25 (depends on 13)

The method of claim 13, wherein said humanized antibody or antigen-binding fragment thereof has the binding characteristics of an antibody produced from a hybridoma cell line having ATCC accession number PTA-4592.