Novel Anti-Coagulation Therapeutics: Agents That Effectively Inhibit Binding of Factor VIIIa (Region 3) With Factor IXa (Region 2) Without Activating Factor X.
Inventor: Dr. S. Paul Bajaj and Dr. Philip J. Fay
Two newly discovered areas, factor VIIIa (Region 3) and factor IXa (Region 2), have been identified that interact during factor X activation. Based on a detailed sequence knowledge of factor VIIIa (Region 3) and factor IXa (Region 2), several novel compositions have been identified which effectively inhibiting blood coagulation by blocking the binding of factor VIIIa with factor IXa in the area of Region 2 and/or Region 3 without activating factor X.
These novel coagulation inhibitors include (i) certain polypeptides that contain 3-10 contiguous amino acids (or a nonpeptidomimetic of said amino acids) which are homologous to recognized sequences contained in factor VIIIa (Region 3) or in factor IXa (Region 2), or (ii) a non-homologous binding polypeptide, preferably a humanized monoclonal antibody, having a binding site that specifically binds to factor VIIIa (Region 3) or factor IXa (Region 2), or (iii) a polynucleotide sequence encoding an amino acid sequence homologous to any one of the aforementioned agents where the polynucleotide is operably linked to a control sequence that allows the polynucleotide to be translated in a mammalian cell.
Methods are described for anti-coagulation treatment of patients as well as for the screening and identification of anti-coagulation therapeutic agents that act by effectively blocking the binding of factor VIIIa (Region 3) with factor IXa Region 2).
(1) Novel anti-coagulation therapeutic agents have been identified which bind to newly discovered regions in factor VIIIa (Region 3) and factor IXa (Region 2) and effectively block factor X activation and blood coagulation. These novel coagulation inhibitors are potentially useful therapeutic products targeted to treatment of patients suffering from cardiovascular disorders (thrombosis, atherosclerosis, restenosis); and,
(2) A sensitive in vitro assay procedure is described that is useful for screening of drug candidates for anti-coagulation activity resulting from inhibition of the binding of factor VIIIa (Region 3) with factor IXa (Region 2) without activation of factor X.
Keywords: anticoagulant, factor X activation, blood clotting, fibrinolysis, hemophilia, factor VIII, factor IX, hemostasis
Patents: PCT Application US/02/01724 (Filed Jan 23,2002): Designating US
Reference Number: SLU-1003