Regulator of complement activation and uses thereof
A potent complement regulator is disclosed. The complement regulator comprises a complement regulatory region connected by a flexible linker to a multifunctional binding region that enables binding to C3b activation/inactivation products and/or oxidation end products, as well as to polyanionic surface markers on host cells. An embodiment of the invention utilizes factor H SCRs 1-4 as the complement regulatory region and factor H SCRs 19 and 20 as the multifunctional binding region, linked together by a poly-Gly linker at least 12 residues in length. Pharmaceutical compositions comprising the complement regulator and methods of using the complement regulator are also disclosed.
1. A complement regulator comprising a complement regulating region that includes a plurality of complement control proteins (CCPs), linked by a flexible linker to a multifunctional binding region that enables binding of the complement regulator to (a) one or more C3b activation/inactivation products, (b) one or more oxidation end products and (c) one or more polyanionic surface markers on host cells, and wherein the flexible linker is of the same length and flexibility as a poly-Gly peptide at least 9, 10, 11 or 12 residues in length.
2. The complement regulator of claim 1 , wherein the CCPs are derived from factor H.
3. The complement regulator of claim 2 , wherein the CCPs are derived from SCRs 1-4 of factor H.
4. The complement regulator of claim 1 , wherein the C3b activation/inactivation products contain thioester domains (TEDs).
5. The complement regulator of claim 4 , wherein the C3b activation/inactivation products are C3b, iC3b, C3dg or C3d.
6. The complement regulator of claim 1 , wherein the polyanionic surface markers on host cells are N-linked glycosyl units with sialic acid end-groups or glycosaminoglycans (GAGs) selected from heparin, heparan sulfate, chondroitin sulfate, dermantan sulfate, keratan sulfate and hyaluronan.
7. The complement regulator of claim 1 , wherein the oxidation end products are malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), carboxyethylpyrrole (CEP), oxidized phosphatidylserine (OxPS), oxidized cardiolipin (OxCL) and phosphocholine (PC).
8. The complement regulator of claim 1 , wherein the multifunctional binding region is derived from SCRs 19 and 20 of factor H.
9. The complement regulator of claim 1 , wherein the linker is of the same length and flexibility as a poly-Gly peptide at least 10, 11 or 12 residues in length.
10. The complement regulator of claim 9 , wherein the linker is a poly-Gly peptide at least 12 residues in length.
11. The complement regulator of claim 1 , comprising, from N- to C-terminus, SCRs 1-4 of factor H, a poly-Gly linker at least 12 residues in length, and SCRs 19-20 of factor H.
12. The complement regulator of claim 11 , wherein the factor H is human factor H.
13. The complement regulator of claim 1 , comprising a polypeptide that is functionally equivalent to SEQ ID NO:2.
14. The complement regulator of claim 13 , wherein the polypeptide sequence has more than 90% sequence identity to that of SEQ ID NO:2.
15. The complement regulator of claim 14 , comprising SEQ ID NO:2.
16. A polypeptide comprising, from N- to C-terminus, SCRs 1-4 of factor H, a poly-Gly linker at least 12 residues in length, and SCRs 19-20 of factor H.
17. The polypeptide of claim 16 , wherein the factor H is human factor H.
18. The polypeptide of claim 17 , comprising SEQ ID NO:2.
19. A pharmaceutical composition comprising the complement regulator of claim 1 and a pharmaceutically acceptable carrier.