Immunoglobulins insertions, deletions, and substitutions

• US 8,883,147 B2
• Filed: 03/18/2013
• Issued: 11/11/2014
• Est. Priority Date: 10/21/2004
• Status: Active Grant

• Current Assignee: Xencor, Inc.
• Original Assignee: Xencor, Inc.
• Inventors: Lazar, Gregory, Dahiyat, Bassil, Dang, Wei, Karki, Sher Bahadur, Vafa, Omid
• Primary Examiner(s): DAHLE, CHUN WU
• Application Number:
  US13/846,527
• Publication Number:
  US 20130202599A1
• Time in Patent Office: 603 Days
• Field of Search: None
• US Class Current: 424/130.1
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 16/2887 against CD20
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/71 Decreased effector function due to an Fc-modification

Abstract

An Fc variant of a parent Fc polypeptide, wherein said Fc variant exhibits altered binding to one or more FcγRs, wherein said Fc variant comprises at least one amino acid insertion in the Fc region of said parent Fc polypeptide.

Claims

1. A method of inhibiting effector activity in a subject, comprising administering to a subject a polypeptide comprising a variant Fc region of a parent Fc region, wherein said variant Fc region comprises a first amino acid substitution at position 236 and a second amino acid substitution at position 328, wherein said first substitution is 236R and said second substitution is 328R, wherein said numbering is according to the EU index in Kabat, wherein the polypeptide is an antibody or an immunoadhesin.

2. A method according to claim 1 wherein said effectors activity includes antibody dependent cell mediated cytotoxicity (ADCC), antibody depending cell mediated phagocytosis (ADCP) and complement dependent cytotoxicity (CDC).

3. A method according to claim 1 wherein said polypeptide exhibits ablated binding to all Fcγ

R receptors.

4. A method according to claim 3 wherein said polypeptide exhibits no detectable binding to Fcγ

RI, Fcγ

RIIa, Fcγ

RIIb, Fcγ

RIIIa(V158) and Fcγ

RIIIb(F158) as measured by a Biacore assay.

5. A method according to claim 1 wherein said polypeptide is an antibody.

6. A method according to claim 5 wherein said antibody is selected from the group consisting of a full-length antibody, an antibody fragment, and an Fc fusion protein.

7. A method according to claim 5 wherein said antibody is conjugated to a toxin.

8. A method according to claim 1 wherein said Fc variant is a variant human IgG1, IgG2, or IgG4 antibody.

9. A method according to claim 1 wherein said subject has cancer.

10. A method according to claim 1 wherein said subject has an autoimmune disorder.

11. A method according to claim 5 wherein said antibody binds to a target antigen selected from the group consisting of TNF-alpha, CTLA-4, IL-6, IL-6R, CD3, C5, CD40, VEGF, FGFR, IgE, and CD19.