Polychain chimeric polypeptides and their uses

Abstract

To provide a multi-chain chimeric polypeptide and use thereof.SOLUTION: Provided is a multi-chain chimeric polypeptide that includes (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 are aggregated via a bond between the first domain and the second domain of the pair of affinity domains. Also provided is a method of using the multi-chain chimeric polypeptides, and a nucleic acid encoding the multi-chain chimeric polypeptides.SELECTED DRAWING: Figure 1

Claims

1. It is a polychain chimeric polypeptide, (a) (i) The first target-binding domain and (ii) A soluble tissue factor domain comprising a sequence that is at least 90% identical to sequence number 1, (iii) The first domain of a pair of affinity domains containing a sequence that is at least 90% identical to sequence number 14 A first chimeric polypeptide, and (b) (i) A second domain of a pair of affinity domains, comprising a sequence that is at least 90% identical to sequence number 28, (ii) Second target binding domain and A second chimeric polypeptide containing The first chimeric polypeptide and the second chimeric polypeptide associate via the binding of the first and second domains of a pair of affinity domains, and (A) The first target-binding domain contains a sequence that is at least 90% identical to SEQ ID NO: 11 and specifically binds to the IL-7 receptor, and the second target-binding domain contains a sequence that is at least 90% identical to SEQ ID NO: 78 and specifically binds to the IL-21 receptor, (B) The first target-binding domain contains a sequence that is at least 90% identical to SEQ ID NO: 78 and specifically binds to the IL-21 receptor, and the second target-binding domain contains a sequence that is at least 90% identical to SEQ ID NO: 11 and specifically binds to the IL-7 receptor, (C) The first target-binding domain comprises a sequence that is at least 90% identical to SEQ ID NO: 16 and specifically binds to the IL-18 receptor, and the second target-binding domain comprises a first sequence that is at least 90% identical to SEQ ID NO: 66 and a second sequence that is at least 90% identical to SEQ ID NO: 68 and specifically binds to the IL-12 receptor, or (D) The first target-binding domain comprises a first sequence that is at least 90% identical to SEQ ID NO: 66 and a second sequence that is at least 90% identical to SEQ ID NO: 68, and specifically binds to the IL-12 receptor; the second target-binding domain comprises a sequence that is at least 90% identical to SEQ ID NO: 16, and specifically binds to the IL-18 receptor; A polychain chimeric polypeptide in which a first chimeric polypeptide and a second chimeric polypeptide associate via the binding of a pair of affinity domains between the first and second domains.

2. The polychain chimeric polypeptide according to claim 1, wherein the first target-binding domain and the soluble tissue factor domain are directly adjacent to each other within the first chimeric polypeptide.

3. The polychain chimeric polypeptide according to claim 1, wherein the first chimeric polypeptide further comprises a linker sequence between the first target-binding domain and the soluble tissue factor domain within the first chimeric polypeptide.

4. The polychain chimeric polypeptide according to claim 1, wherein the first domains of a soluble tissue factor domain and a pair of affinity domains are directly adjacent to each other within the first chimeric polypeptide.

5. The polychain chimeric polypeptide according to claim 1, wherein the first chimeric polypeptide further comprises a linker sequence between a soluble tissue factor domain and a first domain of a pair of affinity domains within the first chimeric polypeptide.

6. The polychain chimeric polypeptide according to claim 1, wherein the second domain and the second target-binding domain of a pair of affinity domains are directly adjacent to each other within the second chimeric polypeptide.

7. The polychain chimeric polypeptide according to claim 1, wherein the second chimeric polypeptide further comprises a linker sequence between the second domain and the second target-binding domain of a pair of affinity domains within the second chimeric polypeptide.

8. The polychain chimeric polypeptide according to claim 1, wherein the first target-binding domain comprises a sequence that is at least 90% identical to SEQ ID NO: 11 and specifically binds to the IL-7 receptor, and the second target-binding domain comprises a sequence that is at least 90% identical to SEQ ID NO: 78 and specifically binds to the IL-21 receptor.

9. The polychain chimeric polypeptide according to claim 8, wherein the first chimeric polypeptide comprises a sequence that is at least 90% identical to sequence number 104, and the second chimeric polypeptide comprises a sequence that is at least 90% identical to sequence number 108.

10. The polychain chimeric polypeptide according to claim 9, wherein the first chimeric polypeptide comprises SEQ ID NO: 104 and the second chimeric polypeptide comprises SEQ ID NO:

108.

11. The polychain chimeric polypeptide according to claim 1, wherein the first target-binding domain comprises a sequence that is at least 90% identical to SEQ ID NO: 78 and specifically binds to the IL-21 receptor, and the second target-binding domain comprises a sequence that is at least 90% identical to SEQ ID NO: 11 and specifically binds to the IL-7 receptor.

12. The polychain chimeric polypeptide according to claim 11, wherein the first chimeric polypeptide comprises a sequence that is at least 90% identical to sequence number 86, and the second chimeric polypeptide comprises a sequence that is at least 90% identical to sequence number 100.

13. The polychain chimeric polypeptide according to claim 12, wherein the first chimeric polypeptide comprises SEQ ID NO: 86, and the second chimeric polypeptide comprises SEQ ID NO:

100.

14. The polychain chimeric polypeptide according to claim 1, wherein the first target-binding domain comprises a sequence that is at least 90% identical to SEQ ID NO: 16 and specifically binds to the IL-18 receptor, and the second target-binding domain comprises a first sequence that is at least 90% identical to SEQ ID NO: 66 and a second sequence that is at least 90% identical to SEQ ID NO: 68 and specifically binds to the IL-12 receptor.

15. The polychain chimeric polypeptide according to claim 14, wherein the first chimeric polypeptide comprises a sequence that is at least 90% identical to SEQ ID NO: 70, and the second chimeric polypeptide comprises a sequence that is at least 90% identical to SEQ ID NO:

74.

16. The polychain chimeric polypeptide according to claim 15, wherein the first chimeric polypeptide comprises SEQ ID NO: 70, and the second chimeric polypeptide comprises SEQ ID NO:

74.

17. The polychain chimeric polypeptide according to claim 1, wherein the first target-binding domain comprises a first sequence that is at least 90% identical to SEQ ID NO: 66 and a second sequence that is at least 90% identical to SEQ ID NO: 68, and specifically binds to the IL-12 receptor, and the second target-binding domain comprises a sequence that is at least 90% identical to SEQ ID NO: 16, and specifically binds to the IL-18 receptor.

18. A composition comprising any one of the polychain chimeric polypeptides described in any one of claims 1 to 17.

19. A pharmaceutical composition for stimulating immune cells or for inducing or increasing the proliferation of immune cells, comprising an effective amount of any one of the polychain chimeric polypeptides described in any one of claims 1 to 17.

20. A pharmaceutical composition for inducing the differentiation of immune cells into memory immune cells or memory-like immune cells, comprising an effective amount of any one of the polychain chimeric polypeptides described in any one of claims 1 to 17.

21. A pharmaceutical composition for killing cancer cells, infected cells, or senescent cells in a target requiring the elimination of cancer cells, infected cells, or senescent cells, comprising a therapeutically effective amount of any of the polychain chimeric polypeptides described in any one of claims 1 to 17.

22. A pharmaceutical composition for treating a subject in need of treatment, comprising a therapeutically effective amount of any of the polychain chimeric polypeptides described in any one of claims 1 to 17.

23. A nucleic acid encoding any of the polychain chimeric polypeptides described in any one of claims 1 to 17.

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