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 comprising the amino acid sequence set forth in SEQ ID NO: 1 or a variant thereof having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1; and
b) an inhibitor of complement activation;
wherein said chimeric molecule inhibits complement activation.
2. The chimeric molecule according to claim 1 , wherein said inhibitor of complement activation is selected from the list consisting of Factor H (FH), GAS6, Protein S, C1-inhibitor (C1-inh), complement component 4 binding protein (C4bp), Factor I (FI), CR1, DAF(CD55), CD59, CR2, or a fragment thereof that inhibits complement activation.
3. The chimeric molecule according to claim 1 , wherein said inhibitor of complement activation is an immunoglobulin molecule or part thereof that is an inhibitor of complement activation.
4. The chimeric molecule according to claim 1 , wherein said ficolin-associated polypeptide comprises the amino acid sequence of residues 20-297 of SEQ ID NO:3, or a functional variant thereof having at least 80% sequence identity to the amino acid sequence of residues 20-297 of SEQ ID NO:3.
5. The chimeric molecule according to claim 1 , wherein said ficolin-associated polypeptide comprises the amino acid sequence of residues 20-380 of SEQ ID NO:1, or a functional variant thereof having at least 80% sequence identity to the amino acid sequence of residues 20-380 of SEQ ID NO:1.
6. The chimeric molecule according to claim 1 , wherein said ficolin-associated polypeptide is in homodimer form.
7. The chimeric molecule according to claim 1 , wherein said ficolin-associated polypeptide consists of the amino acid sequence of residues 20-380 of SEQ ID NO:1.
8. The chimeric molecule according toclaim 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 80% sequence identity to the amino acid sequence of SEQ ID NO: 4.
9. The chimeric molecule according to claim 1 , wherein said ficolin-associated polypeptide and said inhibitor of complement activation are directly or indirectly fused to each other in the form of a fusion protein.
10. A composition comprising the chimeric molecule as defined in claim 1 .
11. 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.
12. The chimeric molecule of claim 3 , wherein said immunoglobulin molecule or part thereof consists of the Fc component of human IgG1, IgG2, IgG3, or IgG4.
13. The chimeric molecule of claim 1 , wherein said chimeric molecule inhibits complement activation when administered to a subject compared to complement activation in an appropriate control subject.