FcγRIIB specific antibodies and methods of use thereof

• US 8,530,627 B2
• Filed: 07/03/2008
• Issued: 09/10/2013
• Est. Priority Date: 08/14/2002
• Status: Active Grant

• Current Assignee: MacroGenics, Inc.
• Original Assignee: MacroGenics, Inc.
• Inventors: Koenig, Scott, Veri, Maria Concetta
• Primary Examiner(s): DAHLE, CHUN WU
• Application Number:
  US12/167,776
• Publication Number:
  US 20090017026A1
• Time in Patent Office: 1,895 Days
• Field of Search: None
• US Class Current: 530/387.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: C07K 16/283 against Fc-receptors, e.g. CD16, CD32, CD64 CD23 C07K16/2851
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• 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 2317/732 Antibody-dependent cellular cytotoxicity [ADCC]

Abstract

The present invention relates to antibodies or fragments thereof that specifically bind FcγRIIB, particularly human FcγRIIB, with greater affinity than said antibodies or fragments thereof bind FcγRIIA, particularly human FcγRIIA. The invention provides methods of enhancing the therapeutic effect of therapeutic antibodies by administering the antibodies of the invention to enhance the effector function of the therapeutic antibodies. The invention also provides methods of enhancing efficacy of a vaccine composition by administering the antibodies of the invention.

Claims

1. An antibody including six CDRs from antibody produced by mouse clone 2B6, having ATCC Accession No. PTA-4591, or an antigen-binding fragment thereof, wherein said antibody is chimeric or humanized of the mouse monoclonal antibody, and wherein said antibody or said antigen-binding fragment thereof comprises a variable domain that specifically binds the extracellular domain of Fcγ

RIIB with greater affinity than said variable domain binds Fcγ

RIIA.

2. The antibody of claim 1, wherein said antibody is humanized.

3. The antibody of claim 1, wherein said antibody is chimeric.

4. The antigen-binding fragment of claim 1, which is an F(ab′

)₂ or F(ab′

) fragment.

5. The antibody of claim 1, further comprising at least one modification in the Fc region.

6. The antibody of claim 5, wherein said Fc region has an altered affinity for an Fcγ

R compared to that of said antibody if comprising a wild-type Fc region.

7. The antibody of claim 5, wherein said Fc region binds Fcγ

RIIIA with a higher affinity compared to that of said antibody if comprising a wild-type Fc region.

8. The antibody of claim 5, wherein said antibody has an antibody mediated effector function that is enhanced relative to that of said antibody if comprising a wild-type Fc region.

9. The antibody of claim 1, wherein said binding to Fcγ

RIIB antagonizes an activity of Fcγ

RIIB selected from the group consisting of;

(A) activating B cell receptor-mediated signaling;

(B) activating of Fcε

RI-induced mast cell activation;

(C) reducing phosphorylation of Fcγ

RIIB; and

(D) recruiting a downstream signaling molecule of the Fcγ

RIIB signal transduction pathway.

10. The antibody of claim 1, wherein said antibody is conjugated to a heterologous polypeptide.

11. The antibody of claim 10, wherein said heterologous polypeptide is a therapeutic agent.

12. The antigen-binding fragment of claim 1, wherein said antigen-binding fragment is conjugated to a heterologous polypeptide.

13. The antigen-binding fragment of claim 12, wherein said heterologous polypeptide is a therapeutic agent.

14. The antibody of claim 11, wherein said therapeutic agent is a cytotoxin.

15. The antigen-binding fragment of claim 13, wherein said therapeutic agent is a cytotoxin.

16. The antibody of claim 14, wherein said cytotoxin is paclitaxel, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, a glucocorticoid, procaine, tetracaine, lidocaine, propranolol, puromycin, epirubicin, or cyclophosphamide.

17. The antigen-binding fragment of claim 15, wherein said cytotoxin is paclitaxel, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, a glucocorticoid, procaine, tetracaine, lidocaine, propranolol, puromycin, epirubicin, or cyclophosphamide.

18. A pharmaceutical composition comprising:

(A) a therapeutically effective amount of an antibody including six CDRs from antibody produced by mouse clone 2B6, having ATCC Accession No. PTA-4591, or an antigen-binding fragment thereof, wherein said antibody is chimeric or humanized of the mouse monoclonal antibody, and wherein said antibody or said antigen-binding fragment thereof comprises a variable domain that specifically binds the extracellular domain of Fcγ

RIIB with greater affinity than said variable domain binds Fcγ

RIIA; and

(B) a pharmaceutically acceptable carrier.

19. The pharmaceutical composition of claim 18, which further comprises:

(C) a cytotoxic antibody that specifically binds a cancer antigen.

20. The pharmaceutical composition of claim 18, wherein said antibody is humanized.

21. The pharmaceutical composition of claim 19, wherein said cytotoxic antibody is a human or humanized antibody.

22. The pharmaceutical composition of claim 18, wherein said composition comprises said antigen-binding fragment which is an F(ab′

)₂ or F(ab′

) fragment.

23. The pharmaceutical composition of claim 18, wherein said antibody comprises at least one modification in the Fc region.

24. The pharmaceutical composition of claim 23, wherein said Fc region has an altered affinity for an Fcγ

R compared to that of said antibody if comprising a wild-type Fc region.

25. The pharmaceutical composition of claim 23, wherein said Fc region binds Fcγ

RIIIA with a higher affinity compared to that of said antibody if comprising a wild-type Fc region.

26. The pharmaceutical composition of claim 23, wherein said antibody exhibits an antibody mediated effector function that is enhanced relative to that of said antibody if comprising a wild-type Fc region.

27. The pharmaceutical composition of claim 18, wherein the binding to Fcγ

RIIB antagonizes an activity of Fcγ

RIIB selected from the group consisting of;

(A) activating B cell receptor-mediated signaling;

(B) activating of Fcε

RI-induced mast cell activation;

(C) reducing phosphorylation of Fcγ

RIIB; and

(D) recruiting a downstream signaling molecule of the Fcγ

RIIB signal transduction pathway.

28. The pharmaceutical composition of claim 18, further comprising one or more additional anti-cancer agents.

29. The pharmaceutical composition of claim 28, wherein said anti-cancer agent is a chemotherapeutic agent or a radiation therapeutic agent.