Interferon-β variants and conjugates
View Patent ↗The present invention provides new interferon β conjugates, methods of preparing such conjugates and the use of such conjugates in therapy, in particular for the treatment of multiple sclerosis.
1. An interferon β polypeptide variant exhibiting an interferon β activity, comprising a variant sequence which differs from the wildtype human interferon β sequence SEQ ID NO:2 in no more than 8 amino acid residues and which comprises the substitutions F111N+R113S/T relative to SEQ ID NO:2.
2. The variant of claim 1 , wherein the variant sequence comprises the substitutions Q49N, Q51S/T, F111N, and R113S/T.
3. The variant of claim 1 , wherein the variant sequence further comprises at least one substitution relative to SEQ ID NO:2 selected from: K19R; K33R; and K45R.
4. The variant of claim 3 , wherein the variant sequence comprises the substitutions K19R, K33R, K45R, Q49N, Q51S/T, F111N, and R113S/T.
5. The variant of claim 1 , wherein the variant sequence further comprises at least one substitution at a position relative to SEQ ID NO:2 selected from: M1; C17; N80; and V101.
6. The variant of claim 5 , wherein the variant sequence comprises the substitutions C17S, Q49N, Q51S/T, F111N, and R113S/T.
7. A polypeptide conjugate exhibiting an interferon β activity, which conjugate comprises
(a) the variant of claim 1 , and
(b) at least one non-polypeptide moiety covalently attached to the variant.
8. The conjugate of claim 7 , wherein the non-polypeptide moiety is selected from: a polymer molecule, a sugar moiety, a lipophilic compound, and an organic derivatizing agent.
9. The conjugate of claim 7 , wherein the non-polypeptide moiety and the variant are directly covalently joined to one another, or are indirectly covalently joined to one another.
10. The conjugate of claim 8 , comprising at least one sugar moiety or at least one polymer molecule covalently attached to the variant.
11. The conjugate of claim 10 , comprising at least one sugar moiety and at least one polymer molecule covalently attached to the variant.
12. The conjugate of claim 11 , wherein the variant sequence comprises the substitutions Q49N, Q51S/T, F111N, and R113S/T.
13. The conjugate of claim 7 , wherein the variant sequence further comprises at least one substitution relative to SEQ ID NO:2 selected from: K19R; K33R; and K45R.
14. The conjugate of claim 13 , wherein the variant sequence comprises the substitutions K19R, K33R, K45R, Q49N, Q51S/T, F111N, and R113S/T.
15. The conjugate of claim 7 , wherein the variant sequence further comprises at least one substitution in a position relative to SEQ ID NO:2 selected from: M1; C17; N80; and V101.
16. The conjugate of claim 15 , wherein the variant sequence comprises the substitutions C17S, Q49N, Q51S/T, F111N, and R113S/T.
17. The conjugate of claim 10 , wherein the sugar moiety is covalently attached to an asparagine residue of the variant.
18. The conjugate of claim 17 , wherein the sugar moiety is covalently attached to an asparagine residue of the variant selected from the group consisting Q49N, N80, and F111N.
19. The conjugate of claim 10 , wherein the polymer molecule is covalently attached to a lysine residue of the variant.
20. The conjugate of claim 10 , wherein the polymer molecule is covalently attached to the N-terminus of the variant.
21. The conjugate of claim 10 , wherein the polymer molecule comprises a linear polyethylene glycol or a branched polyethylene glycol.
22. A method for preparing a conjugate, the method comprising:
providing the variant of claim 1 ;
contacting the variant with a non-polypeptide moiety under conditions conducive for conjugation; and
recovering the conjugate.
23. A composition comprising the variant of claim 1 or the conjugate of claim 7 and a pharmaceutically acceptable diluent, carrier, excipient or adjuvant.
24. A method for treating a mammal with a disease for which interferon β is a useful treatment, comprising administering to the mammal an effective amount of the composition of claim 23 .
25. The method of claim 24 , wherein the disease is multiple sclerosis.
26. The method of claim 24 , wherein the mammal is a human.
27. A method for treating a mammal with a disease for which interferon β is a useful treatment, comprising administering to the mammal an effective amount of the interferon β polypeptide variant of claim 1 .
28. A method for treating a mammal with a disease for which interferon β is a useful treatment, comprising administering to the mammal an effective amount of the interferon β polypeptide variant of claim 2 .
29. A method for treating a mammal with a disease for which interferon β is a useful treatment, comprising administering to the mammal an effective amount of the interferon β polypeptide variant of claim 6 .
30. A method for treating a mammal with a disease for which interferon β is a useful treatment, comprising administering to the mammal an effective amount of the polypeptide conjugate of claim 7 .
31. A method for treating a mammal with a disease for which interferon β is a useful treatment, comprising administering to the mammal an effective amount of the polypeptide conjugate of claim 12 .
32. A method for treating a mammal with a disease for which interferon β is a useful treatment, comprising administering to the mammal an effective amount of the polypeptide conjugate of claim 16 .