Immunoglobulin insertions, deletions, and substitutions

• US 8,399,618 B2
• Filed: 12/23/2011
• Issued: 03/19/2013
• Est. Priority Date: 10/21/2004
• Status: Active Grant

• Current Assignee: Xencor, Inc.
• Original Assignee: Xencor, Inc.
• Inventors: Lazar, Gregory Alan, Dahiyat, Bassil I., Dang, Wei, Karki, Sher Bahadur, Vafa, Omid
• Primary Examiner(s): DAHLE, CHUN WU
• Application Number:
  US13/336,907
• Publication Number:
  US 20120225058A1
• Time in Patent Office: 452 Days
• Field of Search: None
• US Class Current: 530/350
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• 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 16/2803 against the immunoglobulin superfamily
• 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 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/53 Hinge
• 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

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 protein comprising a variant Fc region of a parent Fc polypeptide, wherein said variant Fc region comprises a first substitution at position 328 and a second substitution at or an insertion after position 236, wherein said first substitution is arginine, said second substitution is arginine, and said insertion is arginine, wherein said protein exhibits ablated binding affinity to more than one Fcγ

R as compared to said parent polypeptide and numbering is according to the EU index as in Kabat.

2. The protein of claim 1, wherein said protein is an antibody.

3. The protein of claim 2, wherein said antibody is selected from the group consisting of a human antibody, a humanized antibody, and a monoclonal antibody.

4. The protein of claim 3, wherein said antibody is a humanized.

5. The protein of claim 1, wherein said protein exhibits ablated binding affinity to Fcγ

RI and Fcγ

RIIb.

6. The protein of claim 1, wherein said protein exhibits ablated binding affinity to Fcγ

RIIa and Fcγ

RIIb.

7. The protein of claim 1, wherein said protein exhibits ablated binding affinity to Fcγ

RIIb and Fcγ

RIIIa.

8. The protein of claim 2, wherein said antibody further comprises an engineered glycoform.

9. The protein of claim 2, wherein said antibody has specificity for a target antigen selected from the group consisting of A33, BAFF-R, CA 125, CD5, CD19, CD20, CD30, CD33, CD38, CD40, CD44, CD52, CD123, CD138, CEA, EGFR (ErbB-1), EpCAM, GD2, GD3, Her2/neu (ErbB-2), HM1.24, IGF-1R, IL-5R, IL-6R, integrin alpha5, integrin alpha5/beta1, integrin alpha5/beta3, Lewis Y related carbohydrate, MCAM (melanoma cell adhesion molecule), PSCA (prostate stem cell antigen), PSMA (protage specific membrane antigen), STEAP (six-transmembrane epithelial antigen of the prostate), and TAG-72 (tumor-associated glycoprotein-72).