FcγRIIB specific antibodies and methods of use thereof

• US 8,968,730 B2
• Filed: 07/03/2008
• Issued: 03/03/2015
• Est. Priority Date: 08/14/2002
• Status: Active Grant

• Current Assignee: MacroGenics, Inc.
• Original Assignee: MacroGenics, Inc.
• Inventors: Koenig, Scott, Veri, Maria Concetta, Tuaillon, Nadine
• Primary Examiner(s): DAHLE, CHUN WU
• Application Number:
  US12/167,765
• Publication Number:
  US 20090092610A1
• Time in Patent Office: 2,434 Days
• Field of Search: None
• US Class Current: 424/130.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/283 against Fc-receptors, e.g. CD16, CD32, CD64 CD23 C07K16/2851
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/41 Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/54 F(ab')2
• CPC Class Codes: C07K 2317/71 Decreased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/732 Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

The present invention relates to antibodies or fragments thereof that specifically bind the extracellular domain of FcγRIIB, particularly human FcγRIIB, and block the Fc binding site of human FcγRIIB. The invention provides methods of treating cancer and/or regulating immune complex-mediated cell activation by administering the antibodies of the invention to enhance an immune response. The invention also provides methods of breaking tolerance to an antigen by administering an antigen-antibody complex and an antibody of the invention.

Claims

1. A method of enhancing immune response to an antigen in a patient by blocking negative regulation of immune-complex-triggered activation, wherein said antigen is associated with a cancer or a neoplastic disease or is an antigen of a pathogen, said method comprising administering to said patient:

(i) an antigen-antibody complex; and

(ii) an antibody or an antigen-binding fragment thereof that specifically binds the extracellular domain of human Fcγ

RIIB with greater affinity than human Fcγ

RIIA and inhibits binding to the Fc binding site of human Fcγ

RIIB, wherein said antibody or antigen-binding fragment thereof comprises the six CDRs of antibody produced by clone 2B6 having ATCC Accession No. PTA-4591 or the six CDRs of antibody produced by clone 3H7 having ATCC Accession No. PTA-4592;

to thereby enhance immune response in said patient to said antigen.

2. The method of claim 1, wherein said antibody or fragment thereof is administered prior to administration of said antigen-antibody complex.

3. The method of claim 1, wherein said antibody or fragment thereof is administered concurrently with said antigen-antibody complex.

4. The method of claim 1, wherein said antibody or fragment thereof is administered after administration of said antigen-antibody complex.

5. The method of claim 1, wherein said antigen is an antigen that is associated with a cancer or a neoplastic disease.

6. The method of claim 5, wherein said cancer or neoplastic disease is selected from the group consisting of leukemia, lymphoma, bone and connective tissue sarcoma, brain tumor, breast cancer, adrenal cancer, thyroid cancer, pancreatic cancer, pituitary cancer, eye cancer, vaginal cancer, vulvar cancer, cervical cancer, uterine cancer, ovarian cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder cancer, cholangiocarcinoma, lung cancer, testicular cancer, prostate cancer, penile cancer, oral cancer, basal cancer, salivary gland cancer, pharynx cancer, skin cancer, kidney cancer, Wilms'"'"' tumor, and bladder cancer.

7. The method of claim 6, wherein said cancer or neoplastic disease is breast cancer and said antigen is Her2/neu.

8. The method of claim 5, wherein said antigen that is associated with a cancer or a neoplastic disease is an antigen that is specific to a cancer cell or a neoplastic cell.

9. The method of claim 8, wherein said cancer cell or neoplastic cell is selected from the group consisting of a leukemia cell, a lymphoma cell, a cell of a bone and connective tissue sarcoma, a brain tumor cell, a breast cancer cell, an adrenal cancer cell, a thyroid cancer cell, a pancreatic cancer cell, a pituitary cancer cell, an eye cancer cell, a vaginal cancer cell, a vulvar cancer cell, a cervical cancer cell, a uterine cancer cell, an ovarian cancer cell, an esophageal cancer cell, a stomach cancer cell, a colon cancer cell, a rectal cancer cell, a liver cancer cell, a gallbladder cancer cell, a cholangiocarcinoma cell, a lung cancer cell, a testicular cancer cell, a prostate cancer cell, a penile cancer cell, an oral cancer cell, a basal cancer cell, a salivary gland cancer cell, a pharynx cancer cell, a skin cancer cell, a kidney cancer cell, a Wilms'"'"' tumor cell, and a bladder cancer cell.

10. The method of claim 1, wherein said antigen is an antigen of a pathogen.

11. The method of claim 10, wherein said pathogen is a virus, a bacterium, or a protozoan.

12. The method of claim 1, wherein said antibody or fragment thereof that specifically binds the extracellular domain of human Fcγ

RIIB and inhibits binding to the Fc binding site of human Fcγ

RIIB, comprises an Fc region comprising at least one amino acid modification relative to a wild-type Fc region, such that the modified Fc region has an altered binding affinity to a Fc receptor.

13. The method of claim 12, wherein said altered binding affinity is an increased binding affinity to Fcγ

RIIB or Fcγ

RIII.

14. The method of claim 1, wherein said antibody or fragment thereof that specifically binds the extracellular domain of human Fcγ

RIIB and inhibits binding to the Fc binding site of human Fcγ

RIIB, is a murine monoclonal antibody, a human antibody or a humanized antibody.

15. The method of claim 1, wherein said antibody is the antibody 2B6 (ATCC PTA-4591) or a fragment thereof.

16. The method of claim 1, wherein said antibody is the antibody 3H7 (ATCC PTA-4592) or a fragment thereof.