Engineered heme-binding compositions and uses thereof
Described herein are heme-binding compositions and methods relating to their use, for example methods of treatment of sepsis and rhabdomyolysis.
1. A composition comprising:
an engineered heme-binding fusion protein comprising:
a hemopexin domain comprising a polypeptide having a sequence corresponding to residues 27-213 of SEQ ID NO: 1 or SEQ ID NO: 2; and
a Fc domain comprising the polypeptide sequence of SEQ ID NO: 8, SEQ ID NO: 7, or SEQ ID NO: 17.
2. The composition of claim 1 , wherein the hemopexin domain binds to heme.
3. The composition of claim 1 , wherein the Fc domain is linked to the N-terminus or C-terminus of the hemopexin domain.
4. The composition of claim 1 , wherein the hemopexin domain is a polypeptide comprising the sequence of SEQ ID NO: 1.
5. The composition of claim 1 , wherein the hemopexin domain comprises a polypeptide having a sequence corresponding to:
residues 24-462 of SEQ ID NO: 1;
residues 24-256 of SEQ ID NO: 1;
residues 27-233 of SEQ ID NO: 1;
residues 1-233 of SEQ ID NO: 1;
residues 27-220 of SEQ ID NO: 1;
residues 1-220 of SEQ ID NO: 1;
residues 27-213 of SEQ ID NO: 1;
residues 1-213 of SEQ ID NO: 1;
residues 27-256 of SEQ ID NO: 1;
or residues 1-256 of SEQ ID NO: 1.
6. The composition of claim 5 , wherein the hemopexin domain further comprises a mutation wherein the residues corresponding to residues 220-226 of SEQ ID NO: 1 have been replaced with a polypeptide linker of about 1-10 amino acids in length.
7. The composition of claim 5 , wherein the hemopexin domain further comprises a mutation wherein the residues corresponding to residues 220-226 of SEQ ID NO: 1 have been replaced with the sequence GSGS (SEQ ID NO: 18).
8. The composition of claim 1 , wherein the hemopexin domain is a polypeptide comprising the sequence of SEQ ID NO: 2.
9. The composition of claim 1 , wherein the hemopexin domain comprises a polypeptide having a sequence corresponding to:
residues 27-233 of SEQ ID NO: 2;
residues 1-233 of SEQ ID NO: 2;
residues 27-220 of SEQ ID NO: 2;
residues 1-220 of SEQ ID NO: 2;
residues 27-213 of SEQ ID NO: 2;
residues 1-213 of SEQ ID NO: 2;
residues 27-256 of SEQ ID NO: 2;
or residues 1-256 of SEQ ID NO: 2.
10. The composition of claim 9 , wherein the hemopexin domain further comprises a mutation wherein the residues corresponding to residues 220-226 of SEQ ID NO: 2 have been replaced with a polypeptide linker of about 1-10 amino acids in length.
11. The composition of claim 9 , wherein the hemopexin domain further comprises a mutation wherein the residues corresponding to residues 220-226 of SEQ ID NO: 2 have been replaced with the sequence GSGS (SEQ ID NO: 18).
12. The composition of claim 1 , wherein the engineered heme-binding fusion protein comprises the sequence of SEQ ID NO: 4 or SEQ ID NO: 5.
13. The composition of claim 1 , wherein the second polypeptide domain multimerizes to form a multimeric complex of the engineered heme-binding fusion protein.
14. The composition of claim 13 , wherein the multimeric complex is a dimeric complex.
15. The composition of claim 1 , wherein the second polypeptide domain is linked to the N-terminus or C-terminus of the hemopexin domain via a linker.
16. The composition of claim 1 , wherein the second polypeptide domain is linked to the N-terminus of the hemopexin domain.
17. The composition of claim 1 , wherein the second polypeptide domain is linked to the C-terminus of the hemopexin domain.
18. A pharmaceutical composition comprising the composition of claim 1 and a pharmaceutically acceptable carrier.