Optimized Fc Variants and Methods for their Generation

• US 20130058919A1
• Filed: 02/27/2012
• Published: 03/07/2013
• Est. Priority Date: 03/01/2002
• Status: Active Grant

• Current Assignee: Xencor, Inc.
• Original Assignee: Xencor, Inc.
• Inventors: Lazar, Gregory Alan, Chirino, Arthur J., Dang, Wei, Desjarlais, John R., Doberstein, Stephen Kohl, Hayes, Robert J., Vafa, Omid, Karki, Sher Bahadur
• Granted Patent: US 8,734,791 B2
• Time in Patent Office: Days
• US Class Current: 424/133.1
• 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. An antibody or immunoadhesin of a parent Fc polypeptide, said antibody or immunoadhesin comprising an amino acid substitution at a position selected from the group consisting of 275, 281, 284, 291 and 299, and wherein numbering is according to the EU index.

5. An antibody or immunoadhesin according to claim 1 wherein said antibody or immunoadhesin increases binding affinity to an Fcγ

R as compared to said parent polypeptide, wherein numbering is according to the EU index.

6. An antibody or immunoadhesin according to claim 5 wherein said Fcγ

R is Fcγ

RIIIa.

7. An antibody or immunoadhesin according to claim 6 wherein said Fcγ

RIIIa is a V158 or F158 allotype of Fcγ

RIIIa.

8. An antibody or immunoadhesin according to claim 1 wherein said antibody or immunoadhesin is an antibody.

9. An antibody according to claim 8 wherein said antibody is selected from the group consisting of a human antibody, a humanized antibody, a monoclonal antibody and an antibody fragment.

10. An antibody or immunoadhesin according to claim 1 wherein said antibody or immunoadhesin further comprises an engineered glycoform.

11. An antibody or immunoadhesin according to claim 1 wherein said antibody or immunoadhesin 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, HLA-DR, TNFalpha, MUC18, prostate specific membrane antigen (PMSA) and VEGF.

12. A composition comprising the antibody or immunoadhesin according to claim 1 further comprising a pharmaceutically acceptable carrier.

2. An antibody or immunoadhesin of a parent Fc polypeptide, said antibody or immunoadhesin comprising an amino acid substitution selected from the group consisting of F275L, F275W, G281D, G281K, G281P, G281Y, V284E, V284L, V284N, V284T, V284Y, P291D, P291E, P291G, P291H, P291I, P291Q, P291T, T299A, T299D, T299E, T299F, T299G, T299H, T299I, T299K, T299L, T299L, T299M, T299N, T299P, T299Q, T299R, T299S, T299V, T299W, T299Y, D265Y/N297D/T299L/I332E, N297D/T299E/I332E, N297D/T299F/I332E, N297D/T299H/I332E, N297D/T299E/I332E, N297D/T299V/I332E, wherein numbering is according to the EU index.

3. An antibody or immunoadhesin of a parent Fc polypeptide, said antibody or immunoadhesin comprising an amino acid substitution at position selected from the group consisting of 275, 281, 284, 291 and 299, wherein said antibody or immunoadhesin further comprises an amino acid substitution at a position selected from the group consisting of 221, 222, 224, 227, 228, 230, 231, 223, 233, 234, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 246, 247, 249, 250, 258, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 278, 280, 281, 283, 285, 286, 288, 290, 291, 293, 294, 295, 296, 297, 298, 299, 300, 302, 313, 317, 318, 320, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335 336 and 428, wherein numbering is according to the EU index.

4. An antibody or immunoadhesin according to claim 3 wherein said antibody or immunoadhesin further comprises an amino acid substitution at a position selected from the group consisting of 239 and 332 and wherein numbering is according to the EU index.

13-18. -18. (canceled)