CTLA4 proteins and their uses
The present disclosure relates to CTLA4 proteins and uses of such proteins, for example to treat diseases associated with the dysregulation of immune responses.
1. A variant CTLA4 polypeptide comprising an amino acid sequence having at least 90% sequence identity to amino acids 21 to 112 of SEQ ID NO: 1, wherein the variant polypeptide comprises the amino acid substitution K28H, as compared to SEQ ID NO: 1.
2. The variant CTLA4 polypeptide of claim 1 , which further comprises the amino acid substitution L58G, K93Q, K93M or L96K as compared to a polypeptide of sequence SEQ ID NO:1.
3. The variant CTLA4 polypeptide of claim 1 , which further comprises the amino acid substitution T51N or T51Y as compared to a polypeptide of sequence SEQ ID NO:1.
4. The variant CTLA4 polypeptide of claim 1 , which further comprises the amino acid substitution L61H as compared to a polypeptide of sequence SEQ ID NO:1.
5. The variant CTLA4 polypeptide of claim 4 , which further comprises the amino acid substitution K93Q as compared to a polypeptide of sequence SEQ ID NO: 1.
6. The variant CTLA4 polypeptide of claim 1 , which further comprises the amino acid substitution L104E as compared to a polypeptide of sequence SEQ ID NO:1.
7. The variant CTLA4 polypeptide of claim 1 which is a fusion protein.
8. The variant CTLA4 polypeptide of claim 7 , wherein the fusion protein comprises to CTLA4 extracellular domain linked to an immunoglobulin constant region and optionally a signal sequence.
9. The variant CTLA4 polypeptide of claim 8 , wherein the immunoglobulin constant region is selected from an IgG1, an IgG2, an IgG3 or an IgG4.
10. The variant CTLA4 polypeptide of claim 9 , wherein the immunoglobulin constant region is an IgG1.
11. The variant CTLA4 polypeptide of claim 10 , wherein at least one cysteine residue in the immunoglobulin constant region has been substituted with a serine or a proline.
12. The variant CTLA4 polypeptide of claim 1 , which comprises an amino acid sequence having at least 95% sequence identity to amino acids 21 to 112 of SEQ ID NO:1.
13. The variant CTLA4 polypeptide of claim 1 , which comprises an amino acid sequence having at least 97% sequence identity to amino acids 21 to 112 of SEQ ID NO:1.
14. The variant CTLA4 polypeptide of claim 1 , which comprises an amino acid sequence having at least 99% sequence identity to amino acids 21 to 112 of SEQ NO:1.
15. A variant CTLA4 polypeptide-drug conjugate comprising a variant CTLA4 polypeptide according to claim 1 .
16. A pharmaceutical composition comprising a variant CTLA4 polypeptide according to claim 1 or a variant CTLA4 polypeptide-drug conjugate according to claim 15 , and a pharmaceutically acceptable carrier.
17. A method of treating an autoimmune disease comprising administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 16 .
18. The method of claim 17 , wherein the autoimmune disease is rheumatoid arthritis.
19. The method of claim 17 , wherein the autoimmune disease is idiopathic arthritis.