Medicinal composition usable for preventing and/or treating blood coagulation factor ix abnormality, comprising multispecific antigen binding molecule replacing function of blood coagulation factor viii

Abstract

The present inventors examined the procoagulant activity of a multispecific antigen-binding molecule that functionally substitutes for FVIII using blood and plasma derived from FIX disorder patients. The result showed that multispecific antigen-binding molecules that functionally substitute for FVIII can be used not only as methods for preventing and/or treating bleeding in hemophilia A, acquired hemophilia A, von Willebrand disease, and hemophilia C, which are caused by FVIII dysfunction, but also as methods for preventing and/or treating bleeding in FIX disorders, because of their procoagulant activity. Furthermore, the effect of a FIX formulation could be enhanced by using it in combination with a multispecific antigen-binding molecule that functionally substitutes for FVIII, and it was shown that the combined use is promising as a combination therapy that shows stable hemostatic effects.

1 - 10 . (canceled) 
     
     
         11 . A combination medicament for use in preventing and/or treating blood coagulation factor IX disorder, which is a combination of a multispecific antigen-binding molecule that functionally substitutes for blood coagulation factor VIII and a blood coagulation factor IX formulation. 
     
     
         12 . A method of enhancing the blood coagulation activity of a blood coagulation factor IX formulation in a patient with a blood coagulation factor IX disorder, using a multispecific antigen-binding molecule that functionally substitutes for blood coagulation factor VIII. 
     
     
         13 . A method of preventing or treating a blood coagulation factor IX disorder in a patient, the method comprising administering to the patient a pharmaceutical composition comprising a multispecific antigen-binding molecule that functionally substitutes for blood coagulation factor VIII. 
     
     
         14 . The method of  claim 13 , wherein the multispecific antigen-binding molecule that functionally substitutes for blood coagulation factor VIII is a bispecific antibody that recognizes (a) blood coagulation factor IX and/or activated blood coagulation factor IX, and (b) blood coagulation factor X. 
     
     
         15 . The method of  claim 14 , wherein the bispecific antibody is a bispecific antibody in which a first polypeptide and a third polypeptide form a pair and a second polypeptide and a fourth polypeptide form a pair,
 wherein the first polypeptide consists of an H chain comprising H chain CDR 1, 2, and 3 amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; the second polypeptide consists of an H chain comprising H chain CDR 1, 2, and 3 amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; and the third and fourth polypeptides each consist of a common L chain comprising L chain CDR 1, 2, and 3 amino acid sequences of SEQ ID NOs: 7, 8, and 9, respectively.   
     
     
         16 . The method of  claim 14 , wherein the bispecific antibody is a bispecific antibody in which a first polypeptide and a third polypeptide form a pair and a second polypeptide and a fourth polypeptide form a pair,
 wherein the first polypeptide consists of an H chain comprising the H chain variable region amino acid sequence of SEQ ID NO: 13; the second polypeptide consists of an H chain comprising the H chain variable region amino acid sequence of SEQ ID NO: 14; and the third and fourth polypeptides each consist of a common L chain comprising the L chain variable region amino acid sequence of SEQ ID NO: 15.   
     
     
         17 . The method of  claim 14 , wherein the bispecific antibody is a bispecific antibody in which a first polypeptide and a third polypeptide form a pair and a second polypeptide and a fourth polypeptide form a pair,
 wherein the first polypeptide consists of an H chain comprising the amino acid sequence of SEQ ID NO: 10, the second polypeptide consists of an H chain comprising the amino acid sequence of SEQ ID NO: 11, and the third and fourth polypeptides each consist of a common L chain comprising the amino acid sequence of SEQ ID NO: 12.   
     
     
         18 . The method of  claim 13 , wherein the blood coagulation factor IX disorder is a disease that develops and/or progresses due to a decrease, dysfunction, and/or defect in the activity of blood coagulation factor IX and/or activated blood coagulation factor IX. 
     
     
         19 . The method of  claim 13 , wherein the blood coagulation factor IX disorder is a congenital or acquired disease. 
     
     
         20 . The method of  claim 13 , wherein the blood coagulation factor IX disorder is hemophilia B or blood coagulation factor IX deficiency disease. 
     
     
         21 . The method of  claim 13 , further comprising administering a blood coagulation factor IX formulation to the patient. 
     
     
         22 . The method of  claim 13 , wherein the multispecific antigen-binding molecule enhances the blood coagulation activity of a blood coagulation factor IX formulation. 
     
     
         23 . The method of  claim 13 , wherein the pharmaceutical composition further comprises a blood coagulation factor IX formulation. 
     
     
         24 . The method of  claim 12 , wherein the blood coagulation factor IX disorder is a disease that develops and/or progresses due to a decrease, dysfunction, and/or defect in the activity of blood coagulation factor IX and/or activated blood coagulation factor IX. 
     
     
         25 . The method of  claim 12 , wherein the blood coagulation factor IX disorder is a congenital or acquired disease. 
     
     
         26 . The method of  claim 12 , wherein the blood coagulation factor IX disorder is hemophilia B or blood coagulation factor IX deficiency disease.