Fusion constructs and methods of using thereof
A fusion protein comprising: a first component comprising an antibody, or a fragment or variant thereof; and a second component comprising a cytokine trap or an adenosine deaminase or a fragment or variant thereof. In certain embodiments, the antibody is an anti-PD-1 antibody. In certain embodiments, the antibody binds to a tumor antigen, for example a MUC16 or MUC1 antigen. In certain embodiments, the cytokine trap is a TGF-β trap. A polynucleotide encoding such a fusion protein and a vector comprising such a polynucleotide. A composition comprising the fusion protein. A method of using the composition, including in the treatment of cancer.
1. A fusion protein comprising:
(a) a first component comprising:
a V L region comprising the sequence of any one of SEQ ID NOs: 417-428; and a V H region comprising the sequence of any one of SEQ ID NOs: 390-403; and
(b) a second component that is:
a cytokine trap comprising the sequence of any one of SEQ ID NOs: 14, 141, and 142.
2. The fusion protein of claim 1 , wherein the first component comprises: (a) a VL region comprising the sequence of any one of SEQ ID NOs: 417-428; and (b) a V H region comprising the sequence of any one of SEQ ID NOs: 390-403.
3. The fusion protein of claim 1 , wherein the cytokine trap comprises the sequence of SEQ ID NO: 14.
4. The fusion protein of claim 1 , wherein the first and second components are connected by a linker comprising: (a) (G4S) n , wherein n is 2, 3, 4, 5, or 6 (SEQ ID NO: 555); (b) (Gly) n , wherein n is 6, 7, or 8 (SEQ ID NO: 33); (c) (EAAAK) n , wherein n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 34); (d) A(EAAAK) 4 ALEA(EAAAK) 4 A (SEQ ID NO: 31); and/or (e) a sequence of any one of SEQ ID NOs: 17-34.
5. A polynucleotide encoding the fusion protein of claim 1 .
6. A pharmaceutical composition comprising: (a) the fusion protein of claim 1 , or a polynucleotide encoding the same; and (b) a pharmaceutically-acceptable excipient.
7. The fusion protein of claim 1 , wherein the first component comprises
a V L region comprising the sequence of any one of SEQ ID NOs: 423, 425, and 426; and (ii) a V H region comprising the sequence of SEQ ID NO: 399.
8. The fusion protein of claim 1 , wherein the first component comprises
a V L region comprising the sequence of SEQ ID NO: 426; and a V H region comprising the sequence of SEQ ID NO: 399.
9. The fusion protein of claim 7 , wherein the first component comprises a V L region comprising the sequence of any one of SEQ ID NO: 423.
10. The fusion protein of claim 7 , wherein the first component comprises a V L region comprising the sequence of any one of SEQ ID NO: 425.
11. The fusion protein of claim 7 , wherein the first component comprises a V L region comprising the sequence of any one of SEQ ID NO: 426.
12. The fusion protein of claim 7 , wherein the second component is a cytokine trap comprising the sequence of SEQ ID NO: 14.
13. The fusion protein of claim 7 , wherein the second component is a cytokine trap comprising the sequence of SEQ ID NO: 141.
14. The fusion protein of claim 7 , wherein the second component is a cytokine trap comprising the sequence of SEQ ID NO: 142.
15. The fusion protein of claim 1 wherein:
(a) the first component comprises: (i) a V L region comprising the sequence of SEQ ID NO: 426; and (ii) a V H region comprising the sequence of SEQ ID NO: 399; and
(b) the second component is a cytokine trap comprising the sequence of SEQ ID NO: 14.