CTLA-4 variants

Patent metadata

Field	Value
Publication number	US-9884902-B2
Application number	US-201314399685-A
Country	US
Kind code	B2
Filing date	Mar 11, 2013
Priority date	May 11, 2012
Publication date	Feb 6, 2018
Grant date	Feb 6, 2018

Abstract

Variants of cytotoxic T-lymphocyte antigen 4 (CTLA-4) with high affinity, potency and stability. Formulations of CTLA-4 variants at high concentration for subcutaneous or intravenous administration, e.g. at monthly or less frequent dosage intervals. Use of CTLA-4 variants for treating rheumatoid arthritis and other inflammatory disorders. Fusion of CTLA-4 with IgG Fc having improved stability and longer in vivo half-life.

First claim

What is claimed is:

1. An isolated CTLA-4 polypeptide having greater affinity for binding human CD80, greater potency and/or greater stability compared with wild type CTLA-4 SEQ ID NO: 35, wherein the polypeptide comprises:
amino acid sequence SEQ ID NO: 68, SEQ ID NO: 43, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 36, SEQ ID NO: 42 or SEQ ID NO: 47.

2. A CTLA-4 polypeptide according to claim 1 , wherein the polypeptide has greater affinity than wild type CTLA-4 (SEQ ID NO: 35) for binding human CD86.

3. A CTLA-4 polypeptide according to claim 1 , conjugated to an IgG Fc amino acid sequence.

4. A CTLA-4 polypeptide according to claim 3 , wherein the IgG Fc is a human IgG1 Fc modified to reduce Fc effector function, and comprises a native human IgG1 Fc hinge region.

5. A CTLA-4 polypeptide according to claim 3 , wherein the IgG Fc amino acid sequence comprises SEQ ID NO: 59.

6. A CTLA-4 polypeptide according to claim 3 , wherein the IgG Fc amino acid sequence comprises a human lgG1 Fc region in which one or both of the following groups of residues are substituted as follows:
F at residue 20, E at residue 21, S at residue 117; and
Y at residue 38, T at residue 40, E at residue 42,

the residue numbering being defined with reference to SEQ ID NO: 56.

7. A CTLA-4 polypeptide according to claim 1 , wherein the polypeptide comprises amino acid SEQ ID NO: 68.

8. A CTLA-4 polypeptide according to claim 1 , wherein the polypeptide comprises amino acid SEQ ID NO: 43.

9. A CTLA-4 polypeptide according to claim 1 , wherein the polypeptide comprises amino acid SEQ ID NO: 37.

10. A CTLA-4 polypeptide according to claim 1 , wherein the polypeptide comprises amino acid SEQ ID NO: 38.

11. A CTLA-4 polypeptide according to claim 1 , wherein the polypeptide comprises amino acid SEQ ID NO: 36.

12. A CTLA-4 polypeptide according to claim 1 , wherein the polypeptide comprises amino acid SEQ ID NO: 42.

13. A CTLA-4 polypeptide according to claim 1 , wherein the polypeptide comprises amino acid SEQ ID NO: 47.

14. A CTLA-4 polypeptide according to claim 1 , wherein the polypeptide comprises the sequence of SEQ ID NO: 13.

15. A composition comprising a CTLA-4 polypeptide according to claim 1 , and one or more pharmaceutical excipients.

Assignees

• Medimmune Llc
• Medimmune Ltd

Inventors

• Minter Ralph
• Douthwaite Julie
• Moisan Jacques
• Bowen Michael
• Rust Steven
• Privezentzev Cyril

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title