Optimized Fc variants

• US 8,753,628 B2
• Filed: 06/11/2013
• Issued: 06/17/2014
• Est. Priority Date: 09/27/2002
• Status: Expired due to Term

• Current Assignee: Xencor, Inc.
• Original Assignee: Xencor, Inc.
• Inventors: Lazar, Gregory Alan, Dang, Wei, Desjarlais, John, Karki, Sher Bahadur, Vafa, Omid, Hayes, Robert, Vielmetter, Jost
• Primary Examiner(s): DAHLE, CHUN WU
• Application Number:
  US13/915,608
• Publication Number:
  US 20130273043A1
• Time in Patent Office: 371 Days
• US Class Current: 424/130.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/18 against material from animals or humans
• 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 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 16/30 from tumour cells
• 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 2317/31 multispecific
• 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 2317/40 characterized by post-translational modification
• 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 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/64 comprising a combination of variable region and constant region components
• 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 2317/734 : Complement-dependent cytotoxicity [CDC]
• CPC Class Codes: C07K 2317/77 : Internalization into the cell
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The present invention relates to Fc variants having decreased affinity for FcγRIIb, methods for their generation, Fc polypeptides comprising optimized Fc variants, and methods for using optimized Fc variants.

Claims

1. A method of altering effector function in a subject, comprising administering to the subject a polypeptide comprising an Fc variant of a human parent IgG1 Fc polypeptide, wherein said Fc variant comprises an amino acid substitution in the Fc region of said parent Fc polypeptide at position 243, wherein said numbering is according to the EU index in Kabat.

2. The method according to claim 1, wherein said polypeptide is an antibody.

3. The method according to claim 1, wherein said polypeptide comprises an engineered glycoform.

4. The method according to claim 1, wherein said amino acid substitution is 243L.

5. The method according to claim 1, wherein said amino acid substitution is 243L and said Fc variant exhibits decreased binding to Fcγ

RIIIa as compared to the human parent IgG1 Fc polypeptide.

6. The method according to claim 1, wherein said amino acid substitution is 243E.

7. The method according to claim 1, wherein said amino acid substitution is 243E and said Fc variant exhibits decreased binding to Fcγ

RIIIa as compared to the human parent IgG1 Fc polypeptide.

8. The method according to claim 1, wherein said amino acid substitution is 243W.

9. The method according to claim 1, wherein said amino acid substitution is 243W and said Fc variant exhibits increased binding to Fcγ

RIIIa as compared to the human parent IgG1 Fc polypeptide.

10. The method according to claim 2, wherein said antibody has specificity for a target antigen selected from the group consisting of CD19, CD20, CD22, CD30, CD33, CD40, CD40L, CD52, Her2/neu, EGFR, EpCAM, MUC1, GD3, CEA, CA 125, IgE, HLA-DR, TNFalpha, MUC18, prostate specific membrane antigen (PMSA) and VEGF.

11. The method according to claim 2, wherein said antibody has specificity for Her2/neu.

12. The method according to claim 2, wherein said subject has cancer.

13. The method according to claim 1, wherein said subject has an autoimmune disorder.

14. The method according to claim 1, wherein said subject has an inflammatory disorder.