Chimeric inhibitor molecules of complement activation
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 method of treating a subject suffering from a condition associated with coagulation, thrombotic or a coagulopathic related disease or disorder comprising administering a composition comprising a chimeric molecule of a ficolin-associated polypeptide, wherein said chimeric molecule of a ficolin-associated polypeptide comprises: (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 in a subject suffering from a condition associated with coagulation, thrombotic or a coagulopathic related disease or disorder, and
wherein the 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 (C4 bp), Factor I (FI), CR1, DAF(CD55), CD59, CR2, or a fragment thereof that inhibits complement activation, or an immunoglobulin molecule or part thereof that is an inhibitor of complement activation, and
wherein the condition associated with coagulation, thrombotic or a coagulopathic related disease or disorder is selected from the group consisting of deep venous thrombosis, arterial thrombosis, post-surgical thrombosis, coronary artery bypass graft (CABG), percutaneous transdermal coronary angioplasty (PTCA), platelet deposition stroke, tumor growth, tumor metastasis, angiogenesis, thrombolysis, atherosclerosis, restenosis, sepsis, hypotension, adult respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), disseminated intravascular coagulopathy (DIC), pulmonary embolism, and pathological platelet deposition.
2. The method 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.
3. The method 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.
4. The method according to claim 1 , wherein said ficolin-associated polypeptide is in homodimer form.
5. The method according to claim 1 , wherein said ficolin-associated polypeptide consists of the amino acid sequence of residues 20-380 of SEQ ID NO:1.
6. The method 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 80% sequence identity to the amino acid sequence of SEQ ID NO:4.
7. The method according to claim 1 , wherein said ficolin-associated polypeptide and said inhibitor of complement activation are directly fused to each other in the form of a fusion protein.
8. The method according to 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.
9. The method according to claim 1 , wherein said immunoglobulin molecule or part thereof consists of the Fc component of human IgG1, IgG2, IgG3, or IgG4.
10. The method of claim 1 , wherein the subject is identified as having a high risk for thromboembolic complications.