Chimeric inhibitor molecules of complement activation
Inventors
Garred, Peter • Glue, Tina Hummelshoj • Skjodt, Mikkel-Ole
Assignees
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Publication Number
US-11453709-B2
Publication Date
2022-09-27
Expiration Date
Abstract
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.
Core Innovation
The independent claim describes a method of treating a subject suffering from a condition associated with a coagulation-, thrombotic-, or coagulopathic-related disease or disorder. The method comprises administering a composition containing a chimeric molecule comprising a human ficolin-associated polypeptide having SEQ ID NO:1 or an 80% identity variant and an inhibitor of complement activation. The chimeric molecule inhibits complement activation in the subject, utilizing a ficolin-associated polypeptide that retains lectin-pathway recognition-molecule binding domains but lacks the serine-protease domain.
Chimeric fusion constructs join ficolin-associated polypeptide MAP-1 to complement inhibitors selected from Factor H, GAS6, Protein S, C1-inhibitor, C4-binding protein, Factor I, CR1, DAF (CD55), CD59, CR2, or inhibitory fragments thereof. Factor H constructs optionally incorporate complement-inhibitory N-terminal SCR domains. Disclosed results describe displacement of MASP-2, reduced C4 deposition, and dose-dependent inhibition of lectin-pathway C3 deposition and terminal C9 complex formation by a covalent MAP-1 and Factor H hybrid.
Claims Coverage
The claims identify one independent claim directed to treating a condition associated with coagulation, thrombosis, or coagulopathy using a chimeric ficolin-associated polypeptide, characterized by three inventive features.
Chimeric human ficolin-associated polypeptide
The composition comprises a chimeric molecule containing a human ficolin-associated polypeptide having the amino acid sequence set forth in SEQ ID NO:1 or a variant having at least 80% sequence identity.
Inhibitor of complement activation
The chimeric molecule incorporates an inhibitor of complement activation selected from Factor H, GAS6, Protein S, C1-inhibitor, complement component 4 binding protein (C4bp), Factor I, CR1, DAF (CD55), CD59, CR2, an inhibitory fragment thereof, or an immunoglobulin molecule or part thereof that inhibits complement activation.
Treatment of specified conditions
The method comprises administering the composition to treat a subject suffering from a condition associated with a coagulation, thrombotic, or coagulopathic disease or disorder, including deep venous thrombosis, arterial thrombosis, post-surgical thrombosis, CABG, PTCA, platelet deposition stroke, tumor growth, tumor metastasis, angiogenesis, thrombolysis, atherosclerosis, restenosis, sepsis, hypotension, ARDS, SIRS, DIC, pulmonary embolism, and pathological platelet deposition, wherein the chimeric molecule inhibits complement activation in the subject.
The independent claim combines administration of a chimeric human ficolin-associated polypeptide and a selected complement-activation inhibitor to inhibit complement activation and treat specified coagulation-, thrombotic-, or coagulopathic-related conditions.
Stated Advantages
The chimeric molecule inhibits complement activation in a subject suffering from a condition associated with a coagulation-, thrombotic-, or coagulopathic-related disease or disorder.
The figure summary reports reduced C4 deposition associated with MAP-1-mediated displacement of MASP-2.
Documented Applications
Treatment of coagulation-, thrombotic-, or coagulopathic-related conditions, including 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, pathological platelet deposition, and prevention of thromboembolic complications in high-risk subjects.
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