Single-chain chimeric polypeptides and uses thereof
Provided herein are single-chain chimeric polypeptides that include: (i) a first target-binding domain; (ii) a soluble tissue factor domain; and (iii) a second target-binding domain. Also provided here are methods of using these single-chain chimeric polypeptides and nucleic acids encoding these single-chain chimeric polypeptides.
1. A method of treating a subject having atherosclerosis, the method comprising administering to the subject a therapeutically effective amount of a single-chain chimeric polypeptide comprising:
(i) a first target-binding domain comprising a sequence that is at least 80% identical to SEQ ID NO: 28;
(ii) a soluble tissue factor domain does not have coagulation activity, wherein the soluble tissue factor domain comprises a sequence that is at least 80% identical to SEQ ID NO: 9; and
(iii) a second target-binding domain comprising a sequence that is at least 80% identical to SEQ ID NO: 28,
wherein:
the first target-binding domain and the second target-binding domain bind to a receptor for IL-2; and
the single-chain chimeric polypeptides does not stimulate blood coagulation in a mammal.
2. The method of claim 1 , wherein the first target-binding domain and the soluble tissue factor domain directly abut each other.
3. The method of claim 1 , wherein the single-chain chimeric polypeptide further comprises a linker sequence between the first target-binding domain and the soluble tissue factor domain.
4. The method of claim 1 , wherein the soluble tissue factor domain and the second target-binding domain directly abut each other.
5. The method of claim 1 , wherein the single-chain chimeric polypeptide further comprises a linker sequence between the soluble tissue factor domain and the second target-binding domain.
6. The method of claim 1 , wherein one or both of the first target-binding domain and the second target-binding domain is human IL-2.
7. The method of claim 6 , wherein the first target-binding domain and the second target-binding domain are human IL-2.
8. The method of claim 1 , wherein:
the first target-binding domain comprises a sequence that is at least 90% identical to SEQ ID NO: 28;
the soluble tissue factor domain comprises a sequence that is at least 90% identical to SEQ ID NO: 9; and
the second target-binding domain comprises a sequence that is at least 90% identical to SEQ ID NO: 28.
9. The method of claim 8 , wherein:
the first target-binding domain comprises a sequence that is at least 95% identical to SEQ ID NO: 28;
the soluble tissue factor domain comprises a sequence that is at least 95% identical to SEQ ID NO: 9; and
the second target-binding domain comprises a sequence that is at least 95% identical to SEQ ID NO: 28.
10. The method of claim 9 , wherein:
the first target-binding domain comprises SEQ ID NO: 28;
the soluble tissue factor domain comprises SEQ ID NO: 9; and
the second target-binding domain comprises SEQ ID NO: 28.
11. The method of claim 1 , wherein the soluble tissue factor domain is a soluble human tissue factor domain that does not have coagulation activity.
12. The method of claim 1 , wherein the soluble tissue factor domain comprises or consists of a sequence from a wildtype soluble human tissue factor.
13. The method of claim 1 , wherein the single-chain chimeric polypeptide comprises a sequence that is at least 90% identical to SEQ ID NO: 108.
14. The method of claim 13 , wherein the single-chain chimeric polypeptide comprises a sequence that is at least 95% identical to SEQ ID NO: 108.
15. The method of claim 14 , wherein the single-chain chimeric polypeptide comprises SEQ ID NO: 108.
16. The method of claim 1 , wherein the single-chain chimeric polypeptide comprises a sequence that is at least 90% identical to SEQ ID NO: 110.
17. The method of claim 16 , wherein the single-chain chimeric polypeptide comprises a sequence that is at least 95% identical to SEQ ID NO: 110.
18. The method of claim 17 , wherein the single-chain chimeric polypeptide comprises SEQ ID NO: 110.
19. The method of claim 1 , wherein the single-chain chimeric polypeptide comprises a sequence that is at least 80% identical to SEQ ID NO: 108.
20. The method of claim 1 , wherein the single-chain chimeric polypeptide comprises a sequence that is at least 80% identical to SEQ ID NO: 110.