FcγRIIB specific antibodies and methods of use thereof

• US 8,044,180 B2
• Filed: 07/03/2008
• Issued: 10/25/2011
• 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:
  US12/167,792
• Publication Number:
  US 20090017027A1
• Time in Patent Office: 1,209 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: 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 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 2317/732 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. A mouse monoclonal antibody produced by clone 3H7, having ATCC accession number PTA-4592 or an antigen binding fragment thereof.

2. An antibody including six CDRs from antibody produced by clone 3H7, having ATCC accession number PTA-4592 or an antigen binding fragment thereof, wherein the antibody is a chimeric or humanized version of the mouse monoclonal antibody, and wherein the antibody or 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.

10. The antibody of claim 2, further comprising at least one modification in the Fc region.

11. The antibody of claim 10, wherein said Fc region has an altered affinity for an Fcγ

R.

12. The antibody of claim 10, wherein said Fc region binds Fcγ

RIIIA with a higher affinity than a comparable antibody comprising a wild-type Fc region binds Fcγ

RIIIA.

13. The antibody of claim 10, wherein said antibody has an enhanced antibody mediated effector function relative to a comparable antibody comprising a wild-type Fc region.

14. The antibody of claim 2 which is a humanized version of 3H7or an antigen binding fragment thereof.

15. The antibody of claim 2 which is a chimeric version of 3H7or an antigen binding fragment thereof.

16. The antibody of claim 2 which is a F(ab′

)₂ or a F(ab′

) fragment.

17. The antibody of claim 2 which is a single chain antibody.

18. The antibody of claim 2, wherein said antibody is operably linked to a heterologous polypeptide.

19. The antibody of claim 18, wherein said heterologous polypeptide is an antibody that immunospecifically binds a cell surface receptor.

20. The antibody of claim 18, wherein said heterologous polypeptide is an antibody that immunospecifically binds to a tumor antigen.

21. The antibody of claim 2, wherein said antibody is conjugated to a therapeutic agent.

22. The antibody of claim 21, wherein said therapeutic agent is a cytotoxin.

23. The antibody of claim 22, 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.

24. The antibody of claim 2, wherein said antibody comprises at least one amino acid modification in the Fc region relative to a comparable wild-type Fc region.

3. A hybridoma cell line 3H7, having ATCC accession number PTA-4592.

4. A pharmaceutical composition comprising:

(i.) a therapeutically effective amount of a first antibody including six CDRs from antibody produced by clone 3H7, having ATCC accession number PTA-4592, or an antigen binding fragment thereof, wherein the antibody is a chimeric or humanized version of the murine monoclonal antibody, and wherein the antibody or 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;

(ii.) a second cytotoxic antibody that specifically binds a cancer antigen; and

(iii.) a pharmaceutically acceptable carrier.

5. The pharmaceutical composition of claim 4, wherein said first antibody is a humanized version.

6. The pharmaceutical composition of claim 4 or 5, wherein said second antibody is a human or humanized antibody.

7. The pharmaceutical composition of claim 4, further comprising one or more additional anti-cancer agents.

8. The pharmaceutical composition of claim 7, wherein said anti-cancer agent is a chemotherapeutic agent, a radiation therapeutic agent, a hormonal therapeutic agent, or an immunotherapeutic agent.

25. The pharmaceutical composition of claim 4, wherein said first antibody is a humanized version of 3H7 having ATCC accession number PTA-4592, or an antigen binding fragment thereof.

26. The pharmaceutical composition of claim 4, wherein said first antibody is a chimeric version of 3H7 having ATCC accession number PTA-4592, or an antigen binding fragment thereof.

27. The pharmaceutical composition of claim 4, wherein said first antibody is a fragment, which fragment is a F(ab′

)₂ or F(ab′

) fragment.

9. A pharmaceutical composition comprising:

(i.) a therapeutically effective amount of an antibody including six CDRs from antibody produced by clone 3H7, having ATCC accession number PTA-4592, or an antigen binding fragment thereof, wherein the antibody is a chimeric or humanized version of the murine monoclonal antibody, and wherein the antibody or 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

(ii.) a pharmaceutically acceptable carrier.

28. The pharmaceutical composition of claim 9, wherein said antibody is a humanized version of 3H7 having ATCC accession number PTA-4592, or an antigen binding fragment thereof.

29. The pharmaceutical composition of claim 9, wherein said antibody is a chimeric version of 3H7 having ATCC accession number PTA-4592, or an antigen binding fragment thereof.

30. The pharmaceutical composition of claim 9, wherein said antibody is a F(ab′

)₂ or F(ab′

) fragment.

31. An isolated antibody, or antigen binding fragment thereof, comprising a light chain variable region and a heavy chain variable region from the murine monoclonal antibody produced by clone 3H7, having ATCC accession number PTA-4592, wherein said antibody comprises a variable domain that specifically binds the extracellular domain of Fcγ

RIIB with greater affinity than said variable domain binds Fcγ

RIIA.

32. An isolated antibody, or antigen binding fragment thereof, comprising a light chain variable region from the murine monoclonal antibody produced by clone 3H7, having ATCC accession number PTA-4592, wherein said antibody comprises a variable domain that specifically binds the extracellular domain of Fcγ

RIIB with greater affinity than said variable domain binds Fcγ

RIIA.

34. The antibody of claim 32 or 33, wherein said binding antagonizes at least one activity of Fcγ

RIIB, wherein said at least one activity is selected from the group consisting of activation of B cell receptor-mediated signaling, and activation of Fcε

RI-induced mast cell activation.

35. The antibody of claim 32 or 33 which enhances B cell proliferation, antibody production, intracellular calcium influx, or activity of one or more downstream signaling molecules in the Fcγ

RIIB signal transduction pathway.

36. The antibody of claim 32 or 33 which reduces phosphorylation of Fcγ

RIIB and/or recruitment of one or more downstream signaling molecules in the Fcγ

RIIB signal transduction pathway.

37. The antibody of claim 32 or 33, wherein said antibody is a monoclonal antibody.

38. A humanized version of the antibody of claim 32 or 33, wherein said antibody includes six CDRs produced by clone 3H7 having ATCC accession number PTA-4592.

39. The antibody of claim 32 or 33, wherein said antibody is a fragment, which fragment is a F(ab′

)₂ or F(ab′

) fragment.

40. The antibody of claim 32 or 33 which blocks the binding of an Ig-Fc to Fcγ

RIIB.

33. An isolated antibody, or antigen binding fragment thereof, comprising a heavy chain variable region from the murine monoclonal antibody produced by clone 3H7, having ATCC accession number PTA-4592 wherein said antibody comprises a variable domain that specifically binds the extracellular domain of Fcγ

RIIB with greater affinity than said variable domain binds Fcγ

RIIA.