IMMUNOGLOBULIN VARIANTS AND USES THEREOF

• US 20140294810A1
• Filed: 02/24/2014
• Published: 10/02/2014
• Est. Priority Date: 10/14/2008
• Status: Abandoned Application

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: MENG, Yu-Ju G., LOWMAN, Henry B., YEUNG, Yik Andy, DAMICO, Lisa A., FERRARA, Napaleone
• Application Number:
  US14/188,432
• Publication Number:
  US 20140294810A1
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A01K 2217/07 Animals genetically altered by homologous recombination
• CPC Class Codes: A01K 2267/03 Animal model, e.g. for test or diseases
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/22 against growth factors ; against growth regulators
• 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 2317/56 variable (Fv) region, i.e. VH and/or VL
• 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 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

Variant immunoglobulins with one or more amino acid modifications in the Fc region that have increased in vivo half-lives, and methods of using the same are provided.

Claims

1. A variant IgG comprising a human IgG Fc region comprising two or more amino acid substitutions relative to a wild-type human IgG Fc region at two or more of amino acid residues 251, 252, 307, 308, 378, 428, 430, 434, and 436, numbered according to the EU index as in Kabat, wherein the variant IgG has an increased half-life compared to the half-life of an IgG having the wild-type human IgG Fc region, and wherein at least two of the amino acid substitutions are at amino acid residue 251, 252, 307, 308, 378, 428, 430, 434, or 436, and an amino acid substitution at amino acid residue 251 is a substitution with aspartic acid or glutamic acid, an amino acid substitution at amino acid residue 252 is a substitution with tyrosine, an amino acid substitution at amino acid residue 307 is a substitution with glutamine, an amino acid substitution at amino acid residue 308 is a substitution with proline, an amino acid substitution at amino acid residue 378 is a substitution with valine, an amino acid substitution at amino acid residue 428 is a substitution with leucine, an amino acid substitution at amino acid residue 430 is a substitution with alanine or lysine, an amino acid substitution at amino acid residue 434 is a substitution with alanine, serine or tyrosine, and an amino acid substitution at amino acid residue 436 is a substitution with isoleucine.

2. The variant IgG of claim 1 comprising the amino acid substitution at amino acid 308 with proline and the amino acid substitution at amino acid 434 with alanine.

4. The variant IgG of claim 1 or 3 which has a higher binding affinity for FcRn than the IgG having the wild-type human IgG Fc region.

5. The variant IgG of claim 1 or 3 which has a higher binding affinity for FcRn at pH 6.0 than at pH 7.4.

6. The variant IgG of claim 1 or 3 which has an equal or higher efficacy than the IgG having the wild-type human IgG Fc region.

7. The variant IgG of claim 6 which has a higher efficacy than the IgG having the wild-type human IgG Fc region.

8. The variant IgG of claim 1 or 3 which is a human or humanized IgG.

9. The variant IgG of claim 8 which is IgG₁, IgG₂, IgG₃ or IgG₄.

10. The variant IgG of claim 1 or 3, wherein the IgG Fc region is an IgG₁ Fc region.

11. The variant IgG of claim 1 or 3, wherein the variant IgG is an anti-VEGF antibody.

12. The variant IgG of claim 1 or 3 comprising the heavy chain variable domain comprising SEQ ID NO:

1 and the light chain variable domain comprising SEQ ID NO;

2.

13. A pharmaceutical composition comprising the variant IgG of claim 1 or 3 and a pharmaceutically acceptable carrier.

14. A kit comprising the variant IgG of claim 1 or 3, in a container, and instructions for use.

16. A method of treating tumor in a subject, said method comprising administering to the subject an effective amount of a variant IgG of claim 1 or 3.

17. A method of inhibiting VEGF activity in a subject, said method comprising administering to said subject an effective amount of a variant IgG of claim 1 or 3.

18. The method of claim 17, wherein the VEGF activity is angiogenesis.

19. A method of modulating vascular permeability in a subject, said method comprising administering to said subject an effective amount of a variant IgG of claim 1 or 3.

20. A method of inhibiting or preventing growth of cancer cells in a subject, said method comprising administering to said subject an effective amount of a variant IgG of claim 1 or 3.

21. The method of claim 16, 17, 19 or 20, wherein the variant IgG is administered to the subject every 4 weeks or longer.

3. A variant IgG comprising a human IgG Fc region comprising three or more amino acid substitutions relative to a wild-type human IgG Fc region at three or more of amino acid residues 251, 252, 307, 308, 378, 380, 428, 430, 434, and 436, numbered according to the EU index as in Kabat, wherein the variant IgG has an increased half-life compared to the half-life of an IgG having the wild-type human IgG Fc region, and wherein at least three of the amino acid substitutions are at amino acid residue 251, 252, 307, 308, 378, 380, 428, 430, 434, or 436, and an amino acid substitution at amino acid residue 251 is a substitution with aspartic acid or glutamic acid, an amino acid substitution at amino acid residue 252 is a substitution with tyrosine, an amino acid substitution at amino acid residue 307 is a substitution with glutamine, an amino acid substitution at amino acid residue 308 is a substitution with proline, an amino acid substitution at amino acid residue 378 is a substitution with valine, an amino acid substitution at amino acid residue 380 is a substitution with alanine, an amino acid substitution at amino acid residue 428 is a substitution with leucine, an amino acid substitution at amino acid residue 430 is a substitution with alanine or lysine, an amino acid substitution at amino acid residue 434 is a substitution with alanine, serine, tyrosine or histidine, and an amino acid substitution at amino acid residue 436 is a substitution with isoleucine.

15. A variant IgG₁ comprising a human IgG₁ Fc region comprising amino acid substitutions relative to a wild-type human IgG₁ Fc region at amino acid residues 308 and 434, numbered according to the EU index as in Kabat, wherein the variant IgG₁ has an increased half-life compared to the half-life of an IgG₁ having the wild-type human IgG₁ Fc region, and wherein the amino acid substitution at amino acid residue 308 is a substitution with proline, and the amino acid substitution at amino acid residue 434 is a substitution with alanine.