OPTIMIZED Fc VARIANTS

• US 20150315284A1
• Filed: 04/23/2015
• Published: 11/05/2015
• Est. Priority Date: 11/09/2004
• Status: Abandoned Application

• Current Assignee: Xencor, Inc.
• Original Assignee: Xencor, Inc.
• Inventors: Dang, Wei, Desjarlais, John, Karki, Sher Bahadur, Vafa, Omid, Hayes, Robert, Vielmetter, Jost, Lazar, Gregory Alan
• Application Number:
  US14/694,996
• Publication Number:
  US 20150315284A1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 16/2887 against CD20
• CPC Class Codes: C07K 16/2893 against CD52
• 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 2317/41 Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/524 CH2 domain
• CPC Class Codes: C07K 2317/71 Decreased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/72 Increased 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 2317/90 characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Abstract

The present invention relates to a variant Fc region comprising an amino acid substitution at position 238 of the Fc region as compared to a human parent Fc region, wherein the variant Fc region comprises a 238D substitution, wherein the variant Fc region binds FcγRIIb with increased binding affinity compared to a human parent Fc region.

Claims

1-10. -10. (canceled)

11. A method comprising contacting effector cells expressing Fcγ

RIIb with a polypeptide, wherein said polypeptide binds with greater affinity to the Fcγ

RIIb receptor than a parent polypeptide and increases the inhibitory activity of the Fcγ

RIIb receptor, and wherein said polypeptide comprises an Fc variant of said parent Fc polypeptide and wherein said Fc variant comprises an amino acid substitution P238D as compared to said parent Fc polypeptide, wherein said numbering is according to the EU index.

13. The method according to claim 11, wherein said Fc variant has an affinity for Fcγ

RIIb receptor that is more than 5-fold greater than that of the parent Fc polypeptide.

14. The method according to claim 11, wherein said polypeptide is an antibody.

15. The method according to claim 14, wherein said antibody is selected from the group consisting of a human antibody, a humanized antibody, and a chimeric antibody.

16. The method according to claim 15, wherein said antibody is a humanized antibody.

17. The method according to claim 16, wherein said antibody is a chimeric antibody.

18. The method according to claim 14, wherein said antibody further comprises an engineered glycoform.

19. The method according to claim 11, wherein said polypeptide is an Fc fusion polypeptide comprising said Fc variant.

20. The method according to claim 11, wherein increasing inhibitory activity of the Fcγ

RIIb receptor is used to treat disease.

21. The method according to claim 11, wherein increasing inhibitory activity of the Fcγ

RIIb receptor is used to treat autoimmune disease or inflammatory disease.

22. The method according to claim 11, wherein the amino acid substitution is made by generating a nucleic acid that encodes said variant.

12. A method comprising administering to a patient a polypeptide comprising a variant Fc region comprising an amino acid substitution at position 238 of the Fc region as compared to a human parent Fc region, wherein the variant Fc region comprises a 238D substitution, wherein the variant Fc region binds Fcγ

RIIb with increased binding affinity compared to a human parent Fc region, wherein the numbering is according to the EU index

23. A method of enhancing the binding of an Fc polypeptide to the Fcγ

RIIb receptor, said method comprising substituting in a parent Fc polypeptide the amino acid Pro at position 238 with the amino acid Asp to provide an Fc variant of the parent Fc polypeptide, wherein said numbering is according to the EU index.

24. The method of claim 23, wherein the polypeptide is an antibody.

25. The method according to claim 24, wherein said antibody is selected from the group consisting of a human antibody, a humanized antibody, and a chimeric antibody.

26. The method according to claim 24, wherein said antibody further comprises an engineered glycoform.

27. The method according to claim 23, wherein said polypeptide is an Fc fusion polypeptide comprising said Fc variant.

28. The method according to claim 23, wherein the amino acid substitution is made by generating a nucleic acid that encodes said variant.