Targeting complement factor H for treatment of diseases
The invention provides a CR2-FH molecule comprising a CR2 portion comprising CR2 protein or a fragment thereof and a FH portion comprising a factor H protein or a fragment thereof, and pharmaceutical compositions comprising a CR2-FH molecule. Also provided are methods of using the compositions for treatment diseases in which the alternative complement pathway is implicated, such as age-related macular degeneration, rheumatoid arthritis, and ischemia reperfusion.
1. A pharmaceutical composition comprising a complement receptor 2 (CR2)-factor H (FH) molecule comprising:
a) a CR2 portion comprising a CR2 or a fragment thereof, and
b) a FH portion comprising a FH or a fragment thereof, said FH portion or fragment thereof comprising at least the first four N-terminal short consensus repeat (SCR) domains of FH,
wherein the CR2 portion of the CR2-FH molecule is capable of binding to a CR2 ligand;
wherein the FH portion of the CR2-FH molecule is capable of inhibiting activation of the alternative complement pathway; and
wherein said pharmaceutical composition comprises an amount of said CR2-FH molecule of about 0.01 μg/kg to about 300 mg/kg.
2. The pharmaceutical composition of claim 1 , wherein the CR2 portion comprises at least the first two N-terminal SCR domains of CR2.
3. The pharmaceutical composition of claim 1 , wherein the CR2 portion comprises at least the first four N-terminal SCR domains of CR2.
4. The pharmaceutical composition of claim 1 , wherein the FH portion comprises at least the first five N-terminal SCR domains of FH.
5. The pharmaceutical composition of claim 1 , wherein the CR2-FH molecule comprises two or more CR2 or FH portions.
6. The pharmaceutical composition of claim 5 , wherein the CR2 or the FH portions are tandemly linked.
7. The pharmaceutical composition of claim 1 , wherein the CR2 portion comprises the first four N-terminal SCR domains of CR2 and the FH portion comprises the first five SCR domains of FH.
8. The pharmaceutical composition of claim 7 , wherein the CR2 portion comprises amino acids 23 to 271 of SEQ ID NO:1 and the FH portion comprises amino acids 21 to 320 of SEQ ID NO:2.
9. The pharmaceutical composition of claim 1 , wherein the CR2-FH molecule is a fusion protein.
10. The pharmaceutical composition of claim 1 further comprising a pharmaceutically acceptable carrier.
11. The pharmaceutical composition of claim 10 , wherein the composition is suitable for intraocular, intravenous, intraarterial, sub-cutaneous, intratracheal, or inhalational administration.
12. The pharmaceutical composition of claim 1 , wherein the CR2-FH molecule:
a) forms dimers or multimers; or
b) comprises a derivatized CR2 or FH portion comprising glycosylation, phosphorylation, acetylation, myristoylation, prenylation, palmitation, amidation, and/or addition of glycosylphosphatidyl inositol; or
c) is fused to a compound that increases the half-life of the CR2-FH molecule or reduces immunogenicity.
13. The pharmaceutical composition of claim 12 , wherein the compound is polyethylene glycol or albumin.