Fusion constructs and methods of using thereof
Provided herein is a composition comprising a fusion protein or a fragment or a variant thereof comprising an anti-PD1 antibody or a fragment/variant thereof and a TGF-β trap. Provided herein is a composition comprising a fusion protein or a fragment thereof or a variant thereof comprising an anti-PD1 antibody or a fragment/variant thereof and a ADA2 polypeptide. Also provided herein are methods of using the composition in treating cancer.
1. A fusion protein comprising:
(a) an IgG4 antibody comprising: (i) a first polypeptide comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 6 or 7; (ii) a second polypeptide comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 12 or 13; and (iii) a third polypeptide comprising the amino acid sequence of SEQ ID NO: 146 but with a mutation at position 108 thereof; and
(b) a fourth polypeptide comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 14;
wherein one or more polypeptides of the fusion protein are connected by a linker.
2. The fusion protein of claim 1 , wherein the linker comprises the amino acid sequence of any one of SEQ ID NOs: 17-34.
3. The fusion protein of claim 1 , wherein the third polypeptide comprises an amino acid sequence that differs from the amino acid sequence of SEQ ID NO: 14 only by conservative amino acid substitutions.
4. The fusion protein of claim 1 , wherein the mutation is a S108P mutation.
5. The fusion protein of claim 1 , wherein the linker connects the first polypeptide to the fourth polypeptide.
6. The fusion protein of claim 1 , wherein the first polypeptide comprises an amino acid sequence that differs from the amino acid sequence of SEQ ID NO: 6 or 7 only by conservative amino acid substitutions.
7. The fusion protein of claim 1 , wherein the second polypeptide comprises an amino acid sequence that differs from the amino acid sequence of SEQ ID NO: 12 or 13 only by conservative amino acid substitutions.
8. A pharmaceutical composition comprising: the fusion protein of claim 1 ; and a pharmaceutically acceptable excipient.
9. The fusion protein of claim 1 , comprising: a polypeptide having at least 95% sequence identity with SEQ ID NO: 296; and a polypeptide having at least 95% sequence identity with SEQ ID NO: 295.
10. The fusion protein of claim 1 , comprising: a polypeptide having at least 95% sequence identity with SEQ ID NO: 15 and a polypeptide having at least 95% sequence identity with SEQ ID NO: 294.
11. The fusion protein of claim 1 , comprising: the amino acid sequence of SEQ ID NO: 15; and the amino acid sequence of SEQ ID NO: 294.
12. The fusion protein of claim 1 , comprising: the amino acid sequence of SEQ ID NO: 296; and the amino acid sequence of SEQ ID NO: 295.
13. The fusion protein of claim 1 , wherein the first polypeptide comprises the amino acid sequence of SEQ ID NO: 6 or 7.
14. The fusion protein of claim 1 , wherein the second polypeptide comprises the amino acid sequence of SEQ ID NO: 12 or 13.
15. The fusion protein of claim 1 , wherein the fourth polypeptide comprises the amino acid sequence of SEQ ID NO: 14.