Optimized fc variants and methods for their generation

• US 8,734,791 B2
• Filed: 02/27/2012
• Issued: 05/27/2014
• Est. Priority Date: 03/01/2002
• Status: Expired due to Term

• Current Assignee: Xencor, Inc.
• Original Assignee: Xencor, Inc.
• Inventors: Lazar, Gregory Alan, Chirino, Arthur J., Dang, Wei, Desjarlais, John R., Doberstein, Stephen K., Hayes, Robert J., Karki, Sher Bahadur, Vafa, Omid
• Primary Examiner(s): DAHLE, CHUN WU
• Application Number:
  US13/406,347
• Publication Number:
  US 20130058919A1
• Time in Patent Office: 820 Days
• Field of Search: None
• US Class Current: 424/130.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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 16/22 against growth factors ; against growth regulators
• CPC Class Codes: C07K 16/283 against Fc-receptors, e.g. CD16, CD32, CD64 CD23 C07K16/2851
• 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 16/3015 Breast
• CPC Class Codes: C07K 16/32 : against translation products of oncogenes
• 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 2317/52 : Constant or Fc region; Isotype
• 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

Abstract

The present invention relates to optimized Fc variants, methods for their generation, and antibodies and Fc fusions comprising optimized Fc variants.

Claims

1. A method of decreasing antibody-dependent cell-mediated cytotoxicity (ADCC) in a human comprising administering to a human a composition comprising a variant antibody of a human parent antibody which variant mediates antibody-dependent cell-mediated cytotoxicity (ADCC) in the presence of human peripheral blood mononuclear cells less effectively than the parent antibody, wherein said variant antibody comprises an amino acid substitution at position 328 in the Fc region, wherein numbering is according to the EU index.

2. The method of claim 1, wherein said amino acid substitution is selected from the group consisting of 328A, 328E, 328F, 328H, 328M, 328N, and 328Q.

3. The method of claim 1, wherein said amino acid substitution is 328F.

4. The method of claim 1, wherein said variant antibody is a variant IgG antibody.

5. The method of claim 4, wherein said variant IgG antibody is a variant IgG1 antibody.

6. The method of claim 1, wherein said variant antibody is selected from the group consisting of a human antibody, a humanized antibody, and a monoclonal antibody.

7. The method of claim 6, wherein said variant antibody is a humanized antibody.

8. The method of claim 1, wherein said variant antibody comprises an engineered glycoform.

9. The method of claim 1, wherein said variant 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, TNF-alpha, MUC18, prostate specific membrane antigen (PMSA), VEGF, CTLA-4, IL-6, IL-6R, CD3, C5, FGFR-3, and IgE.

10. The method of claim 9, wherein said variant antibody has specificity for the target antigen CD 19.

11. A method of decreasing antibody-dependent cell-mediated cytotoxicity (ADCC) in a human comprising administering to a human a composition comprising a variant antibody of a human parent antibody which variant mediates antibody-dependent cell-mediated cytotoxicity (ADCC) in the presence of human peripheral blood mononuclear cells less effectively than the parent antibody, wherein said variant antibody comprises an amino acid substitution 328F in the Fc region, wherein numbering is according to the EU index.