Chimeric inhibitor molecules of complement activation
View Patent ↗The present invention relates to novel chimeric molecules of ficolin-associated polypeptides, such as fusion polypeptides for the use in the treatment of conditions associated with inflammation, apoptosis, autoimmunity, coagulation, thrombotic or coagulopathic related diseases. The present invention further relates to nucleic acid molecules encoding such fusion polypeptides, vectors and host cells used in the production of the fusion polypeptides.
1. A chimeric molecule of a ficolin-associated polypeptide comprising:
a) a human ficolin-associated polypeptide (FAP) comprising the amino acid sequence set forth in SEQ ID NO:1 or a variant thereof having at least 90% sequence identity to the full length amino acid sequence set forth in SEQ ID NO:1 wherein the FAP variant retains FAP activity; and
b) a second modulator of complement activity, wherein said second modulator of complement activity is Factor H (FH) or a fragment thereof that inhibits complement activition;
wherein said chimeric molecule inhibits complement activation;
and wherein the C-terminus of the ficolin-associated polypeptide is directly or indirectly fused to the N-terminus of the second modulator of complement activity.
2. The chimeric molecule according to claim 1 , wherein said ficolin-associated polypeptide comprises the amino acid sequence 20-297 of SEQ ID NO:3.
3. The chimeric molecule according to claim 1 , wherein said ficolin-associated polypeptide comprises the amino acid sequence 20-380 of SEQ ID NO:1.
4. The chimeric molecule according to claim 1 , wherein said ficolin-associated polypeptide is in homodimer form.
5. The chimeric molecule according to claim 1 , wherein said ficolin-associated polypeptide consists of the amino acid sequence 20-380 of SEQ ID NO 1.
6. The chimeric molecule according to claim 1 , wherein said ficolin-associated polypeptide comprises the amino acid sequence of SEQ ID NO:4 or variants or immunologic fragments thereof having at least 90% sequence identity to the full length amino acid sequence set forth in SEQ ID NO: 4, wherein the functional variant retains FAP activity.
7. A composition comprising the chimeric molecule as defined in claim 1 .
8. The chimeric molecule of claim 1 , wherein said inhibitor of complement activation is Factor H, or a fragment thereof that inhibits complement activation, wherein said fragment of Factor H comprises at least the first four SCR domains of Factor H.