Multi-chain chimeric polypeptides and uses thereof
Provided herein are multi-chain chimeric polypeptides that include: (a) a first chimeric polypeptide including a first target-binding domain, a soluble tissue factor domain, and a first domain of a pair of affinity domains; and (b) a second chimeric polypeptide including a second domain of a pair of affinity domains and a second target-binding domain, where the first chimeric polypeptide and the second chimeric polypeptide associate through the binding of the first domain and the second domain of the pair of affinity domains. Also provided here are methods of using these multi-chain chimeric polypeptides and nucleic acids encoding these multi-chain chimeric polypeptides.
1. A multi-chain chimeric polypeptide comprising:
(a) a first chimeric polypeptide comprising:
(i) a first target-binding domain;
(ii) a soluble tissue factor domain comprising a sequence that is at least 80% identical to SEQ ID NO: 1; and
(iii) a first domain of a pair of affinity domains comprising a sequence that is at least 80% identical to SEQ ID NO: 14; and
(b) a second chimeric polypeptide comprising:
(i) a second domain of a pair of affinity domains comprising a sequence that is at least 80% identical to SEQ ID NO: 28; and
(ii) a second target-binding domain,
wherein the first chimeric polypeptide and the second chimeric polypeptide associate through the binding of the first domain and the second domain of the pair of affinity domains; and
wherein (A) the first target-binding domain comprises a sequence that is at least 80% identical to SEQ ID NO: 11 and the second target-binding domain comprises a sequence that is at least 80% identical to SEQ ID NO: 78, or (B) the first target-binding domain comprises a sequence that is at least 80% identical to SEQ ID NO: 78 and the second target-binding domain comprises a sequence that is at least 80% identical to SEQ ID NO: 11.
2. The multi-chain chimeric polypeptide of claim 1 , wherein the first target-binding domain and the soluble tissue factor domain directly abut each other in the first chimeric polypeptide.
3. The multi-chain chimeric polypeptide of claim 1 , wherein the first chimeric polypeptide further comprises a linker sequence between the first target-binding domain and the soluble tissue factor domain in the first chimeric polypeptide.
4. The multi-chain chimeric polypeptide of claim 1 , wherein the soluble tissue factor domain and the first domain of the pair of affinity domains directly abut each other in the first chimeric polypeptide.
5. The multi-chain chimeric polypeptide of claim 1 , wherein the first chimeric polypeptide further comprises a linker sequence between the soluble tissue factor domain and the first domain of the pair of affinity domains in the first chimeric polypeptide.
6. The multi-chain chimeric polypeptide of claim 1 , wherein the second domain of the pair of affinity domains and the second target-binding domain directly abut each other in the second chimeric polypeptide.
7. The multi-chain chimeric polypeptide of claim 1 , wherein second chimeric polypeptide further comprises a linker sequence between the second domain of the pair of affinity domains and the second target-binding domain in the second chimeric polypeptide.
8. The multi-chain chimeric polypeptide of claim 1 , wherein the soluble tissue factor domain is a soluble human tissue factor domain.
9. The multi-chain chimeric polypeptide of claim 1 , wherein the first target-binding domain comprises a sequence that is at least 80% identical to SEQ ID NO: 11 and the second target-binding domain comprises a sequence that is at least 80% identical to SEQ ID NO: 78.
10. The multi-chain chimeric polypeptide of claim 1 , wherein the first chimeric polypeptide comprises a sequence that is at least 80% identical to SEQ ID NO: 104 and the second chimeric polypeptide comprises a sequence that is at least 80% identical to SEQ ID NO: 108.
11. The multi-chain chimeric polypeptide of claim 1 , wherein the first chimeric polypeptide comprises a sequence that is at least 90% identical to SEQ ID NO: 104 and the second chimeric polypeptide comprises a sequence that is at least 90% identical to SEQ ID NO: 108.
12. The multi-chain chimeric polypeptide of claim 1 , wherein the first chimeric polypeptide comprises a sequence that is at least 95% identical to SEQ ID NO: 104 and the second chimeric polypeptide comprises a sequence that is at least 95% identical to SEQ ID NO: 108.
13. The multi-chain chimeric polypeptide of claim 12 , wherein the first chimeric polypeptide comprises a sequence of SEQ ID NO: 104 and the second chimeric polypeptide comprises a sequence of SEQ ID NO: 108.
14. The multi-chain chimeric polypeptide of claim 1 , wherein the first chimeric polypeptide comprises a sequence of SEQ ID NO: 106 and the second chimeric polypeptide comprises a sequence of SEQ ID NO: 110.
15. A composition comprising the multi-chain chimeric polypeptide of claim 1 .
16. The composition of claim 15 , wherein the composition is a pharmaceutical composition.
17. The multi-chain chimeric polypeptide of claim 1 , wherein the first target-binding domain comprises a sequence that is at least 80% identical to SEQ ID NO: 78 and the second target-binding domain comprises a sequence that is at least 80% identical to SEQ ID NO: 11.
18. The multi-chain chimeric polypeptide of claim 1 , wherein:
the first target-binding domain comprises a sequence that is at least 90% identical to SEQ ID NO: 11;
the soluble tissue factor domain comprises a sequence that is at least 90% identical to SEQ ID NO: 1;
the first domain of the pair of affinity domains comprises a sequence that is at least 90% identical to SEQ ID NO: 14;
the second target-binding domain comprises a sequence that is at least 90% identical to SEQ ID NO: 78; and
the second domain of the pair of affinity domains comprises a sequence that is at least 90% identical to SEQ ID NO: 28.
19. The multi-chain chimeric polypeptide of claim 1 , wherein:
the first target-binding domain comprises a sequence that is at least 95% identical to SEQ ID NO: 11;
the soluble tissue factor domain comprises a sequence that is at least 95% identical to SEQ ID NO: 1;
the first domain of the pair of affinity domains comprises a sequence that is at least 95% identical to SEQ ID NO: 14;
the second target-binding domain comprises a sequence that is at least 95% identical to SEQ ID NO: 78; and
the second domain of the pair of affinity domains comprises a sequence that is at least 95% identical to SEQ ID NO: 28.
20. The multi-chain chimeric polypeptide of claim 1 , wherein:
the first target-binding domain comprises SEQ ID NO: 11;
the soluble tissue factor domain comprises SEQ ID NO: 1;
the first domain of the pair of affinity domains comprises SEQ ID NO: 14;
the second target-binding domain comprises SEQ ID NO: 78; and
the second domain of the pair of affinity domains comprises SEQ ID NO: 28.
21. The multi-chain chimeric polypeptide of claim 1 , wherein:
the first target-binding domain comprises a sequence that is at least 90% identical to SEQ ID NO: 78;
the soluble tissue factor domain comprises a sequence that is at least 90% identical to SEQ ID NO: 1;
the first domain of the pair of affinity domains comprises a sequence that is at least 90% identical to SEQ ID NO: 14;
the second target-binding domain comprises a sequence that is at least 90% identical to SEQ ID NO: 11; and
the second domain of the pair of affinity domains comprises a sequence that is at least 90% identical to SEQ ID NO: 28.
22. The multi-chain chimeric polypeptide of claim 1 , wherein:
the first target-binding domain comprises a sequence that is at least 95% identical to SEQ ID NO: 78;
the soluble tissue factor domain comprises a sequence that is at least 95% identical to SEQ ID NO: 1;
the first domain of the pair of affinity domains comprises a sequence that is at least 95% identical to SEQ ID NO: 14;
the second target-binding domain comprises a sequence that is at least 95% identical to SEQ ID NO: 11; and
the second domain of the pair of affinity domains comprises a sequence that is at least 95% identical to SEQ ID NO: 28.
23. The multi-chain chimeric polypeptide of claim 1 , wherein:
the first target-binding domain comprises SEQ ID NO: 78;
the soluble tissue factor domain comprises SEQ ID NO: 1;
the first domain of the pair of affinity domains comprises SEQ ID NO: 14;
the second target-binding domain comprises SEQ ID NO: 11; and
the second domain of the pair of affinity domains comprises SEQ ID NO: 28.
24. The multi-chain chimeric polypeptide of claim 1 , wherein the first chimeric polypeptide comprises a sequence that is at least 80% identical to SEQ ID NO: 86 and the second chimeric polypeptide comprises a sequence that is at least 80% identical to SEQ ID NO: 100.
25. The multi-chain chimeric polypeptide of claim 1 , wherein the first chimeric polypeptide comprises a sequence that is at least 90% identical to SEQ ID NO: 86 and the second chimeric polypeptide comprises a sequence that is at least 90% identical to SEQ ID NO: 100.
26. The multi-chain chimeric polypeptide of claim 1 , wherein the first chimeric polypeptide comprises a sequence that is at least 95% identical to SEQ ID NO: 86 and the second chimeric polypeptide comprises a sequence that is at least 96% identical to SEQ ID NO: 100.
27. The multi-chain chimeric polypeptide of claim 1 , wherein the first chimeric polypeptide comprises SEQ ID NO: 86 and the second chimeric polypeptide comprises SEQ ID NO: 100.
28. The multi-chain chimeric polypeptide of claim 1 , wherein the first chimeric polypeptide comprises SEQ ID NO: 88 and the second chimeric polypeptide comprises SEQ ID NO: 102.