CTLA4 proteins and their uses
View Patent ↗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 pharmaceutical composition suitable for administration to a human patient comprising a therapeutically effective amount of a variant CTLA4 polypeptide or a polypeptide-drug conjugate comprising said variant CTLA4 polypeptide and a pharmaceutically acceptable carrier, wherein said variant CTLA4 polypeptide comprises an amino acid sequence having at least 90% sequence identity to amino acids 21 to 112 of SEQ ID NO:1 and comprises the amino acid substitution A29H as compared to a polypeptide of sequence SEQ ID NO:1.
2. The pharmaceutical composition of claim 1 , wherein the variant CTLA4 polypeptide comprises one or more of the amino acid substitutions selected from K28H, K28T, T51N, T51Y, L58G, K93M, and L96K as compared to a polypeptide of sequence SEQ ID NO:1.
3. The pharmaceutical composition of claim 2 wherein the variant CTLA4 polypeptide comprises the amino acid substitution K28H.
4. The pharmaceutical composition of claim 3 where the variant CTLA4 polypeptide comprises the amino acid substitution K93Q as compared to a polypeptide of SEQ ID NO:1.
5. The pharmaceutical composition of claim 3 where the variant CTLA4 polypeptide comprises the amino acid substitution L61H as compared to a polypeptide of SEQ ID NO:1.
6. The pharmaceutical composition of claim 2 where the variant CTLA4 polypeptide comprises the amino acid substitution K28T.
7. The pharmaceutical composition of claim 6 where the variant CTLA4 polypeptide comprises the amino acid substitution L61A as compared to a polypeptide of SEQ ID NO:1.
8. The pharmaceutical composition of claim 7 where the variant CTLA4 polypeptide comprises the amino acid substitution K93Q as compared to a polypeptide of SEQ ID NO:1.
9. The pharmaceutical composition of claim 1 , wherein the variant CTLA4 polypeptide comprises one or more of the amino acid substitutions selected from M53F, M54W, M54Y, L58A, L58N, L58Q, L61A, L61H, L61Y, K93I, K93V, L96R, L104H, L104M, and L104Y as compared to a polypeptide of sequence SEQ ID NO:1.
10. The pharmaceutical composition of claim 1 , wherein the variant CTLA4 polypeptide comprises the amino acid substitution L104E as compared to a polypeptide of sequence SEQ ID NO:1.
11. The pharmaceutical composition of claim 1 , wherein the variant CTLA4 polypeptide comprises an amino acid sequence having at least 95% sequence identity to amino acids 21 to 112 of SEQ ID NO:1.
12. The pharmaceutical composition of claim 1 , wherein the variant CTLA4 polypeptide comprises an amino acid sequence having at least 97% sequence identity to amino acids 21 to 112 of SEQ ID NO:1.
13. The pharmaceutical composition of claim 1 , wherein the variant CTLA4 polypeptide comprises an amino acid sequence having up to 8 substitutions as compared to amino acids 21 to 112 of SEQ ID NO:1.
14. The pharmaceutical composition of claim 1 , wherein the variant CTLA4 polypeptide comprises an amino acid sequence having up to 5 substitutions as compared to amino acids 21 to 112 of SEQ ID NO:1.
15. The pharmaceutical composition of claim 1 , wherein the variant CTLA4 polypeptide is a fusion protein.
16. The pharmaceutical composition of claim 15 , wherein the fusion protein comprises an amino acid sequence having at least 90% sequence identity to amino acids 1 to 124 of SEQ ID NO:1 operably linked to an immunoglobulin constant region and optionally a signal sequence.
17. The pharmaceutical composition of claim 16 , wherein the amino acid sequence having at least 90% sequence identity to amino acids 1 to 124 of SEQ ID NO:1 and the immunoglobulin constant region are linked by way of a hinge region in the immunoglobulin.
18. The pharmaceutical composition of claim 16 , wherein the immunoglobulin constant region is an IgG1.
19. The pharmaceutical composition of claim 1 , in which the CTLA4 variant polypeptide is not conjugated to a drug.
20. The pharmaceutical composition of claim 1 , which comprises said polypeptide-drug conjugate.
21. 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 A29H and one or more of the amino acid substitutions K28H, K28T and L96K as compared to the polypeptide of SEQ ID NO:1.
22. The variant CTLA4 polypeptide of claim 21 , which comprises the amino acid substitution K28H as compared to a polypeptide of sequence SEQ ID NO:1.
23. The variant CTLA4 polypeptide of claim 22 , which comprises the amino acid substitution K93Q as compared to a polypeptide of sequence SEQ ID NO:1.
24. The variant CTLA4 polypeptide of claim 21 , which comprises the amino acid substitution K28T as compared to a polypeptide of sequence SEQ ID NO:1.
25. The variant CTLA4 polypeptide of claim 24 , which comprises the amino acid substitution K93Q as compared to a polypeptide of sequence SEQ ID NO:1.
26. The variant CTLA4 polypeptide of claim 21 , which comprises the amino acid substitution L96K as compared to a polypeptide of sequence SEQ ID NO:1.
27. The variant CTLA4 polypeptide of claim 26 , which comprises the amino acid substitution K93Q as compared to a polypeptide of sequence SEQ ID NO:1.
28. The variant CTLA4 polypeptide of claim 21 , which comprises the amino acid substitution L104E as compared to a polypeptide of SEQ ID NO:1.
29. The variant CTLA4 polypeptide of claim 21 , which comprises the amino acid substitution L61H as compared to a polypeptide of SEQ ID NO:1.
30. The variant CTLA4 polypeptide of claim 21 , which comprises the amino acid substitution L61A as compared to a polypeptide of SEQ ID NO:1.
31. The variant CTLA4 polypeptide of claim 22 , which comprises the amino acid substitution L61H as compared to a polypeptide of SEQ ID NO:1.
32. The variant CTLA4 polypeptide of claim 22 , which comprises the amino acid substitution L61A as compared to a polypeptide of SEQ ID NO:1.
33. The variant polypeptide of claim 21 , which comprises an amino acid sequence having at least 95% sequence identity to amino acids 21 to 112 of SEQ ID NO:1.
34. The variant CTLA4 polypeptide of claim 21 , which comprises an amino acid sequence having up to 8 substitutions as compared to amino acids 21 to 112 of SEQ ID NO:1.
35. The variant CTLA4 polypeptide of claim 21 , which comprises an amino acid sequence having up to 5 substitutions as compared to amino acids 21 to 112 of SEQ ID NO:1.
36. The variant CTLA4 polypeptide of claim 21 which is a fusion protein.
37. The variant CTLA4 polypeptide of claim 36 , wherein the fusion protein comprises an amino acid sequence having at least 90% sequence identity to amino acids 1 to 124 of SEQ ID NO:1 operably linked to an immunoglobulin constant region and optionally a signal sequence.
38. The variant CTLA4 polypeptide of claim 37 , wherein the amino acid sequence having at least 90% sequence identity to amino acids 1 to 124 of SEQ ID NO:1 and the immunoglobulin constant region are linked by way of a hinge region in the immunoglobulin.
39. The CTLA4 protein of claim 38 , wherein the immunoglobulin constant region is an IgG 1.
40. A polypeptide-drug conjugate comprising a variant CTLA4 polypeptide according to claim 21 .
41. 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 1 , a CTLA4 polypeptide according to claim 21 , or a CTLA4 polypeptide-drug conjugate according to claim 40 .
42. The pharmaceutical composition of claim 2 , wherein the variant CTLA4 polypeptide further comprises the amino acid substitution T51N.
43. The pharmaceutical composition of claim 1 , wherein said therapeutically effective amount is suitable for treatment of an autoimmune disease.