Factor VIII-Fc Chimeric and Hybrid Polypeptides, and Methods of Use Thereof

Abstract

The present invention provides methods of administering Factor VIII; methods of administering chimeric and hybrid polypeptides comprising Factor VIII; chimeric and hybrid polypeptides comprising Factor VIII; polynucleotides encoding such chimeric and hybrid polypeptides; cells comprising such polynucleotides; and methods of producing such chimeric and hybrid polypeptides using such cells.

1 - 110 . (canceled) 
     
     
         111 . A method for treating hemophilia in a human subject in need thereof comprising administering to the subject multiple doses of a chimeric is Factor VIII (FVIII) polypeptide at a dosing interval of at least three days between two doses of the chimeric FVIII polypeptide,
 wherein each of the multiple doses is about 25 IU/kg to about 100 IU/kg and wherein the chimeric FVIII polypeptide comprises FVIII and an FcRn binding partner (FcRn BP).   
     
     
         112 . The method of  claim 111 , wherein the subject has hemophilia A. 
     
     
         113 . The method of  claim 111 , wherein the administration is for prophylaxis of the bleeding episode or for tailored prophylaxis. 
     
     
         114 . The method of  claim 111 , wherein a trough level of plasma Factor VIII:C in the subject after the administration is maintained above 1 IU/dl. 
     
     
         115 . The method of  claim 111 , wherein each of the multiple doses is 25 IU/kg, 30 IU/kg, 35 IU/kg, 40 IU/kg, 45 IU/kg, 50 IU/kg, 55 IU/kg, 60 IU/kg, or 64 IU/kg. 
     
     
         116 . The method of  claim 111 , wherein the dosing interval is three days, four days, five days, six days, or seven days. 
     
     
         117 . The method of  claim 111 , wherein the dosing interval is about twice a week. 
     
     
         118 . The method of  claim 111 , wherein each of the multiple doses is about 65 IU/kg. 
     
     
         119 . The method of  claim 118 , wherein the dosing interval is about four days. 
     
     
         120 . The method of  claim 111 , comprising administering to the subject twice weekly, a first dose of about 25 IU/kg to about 65 IU/kg the chimeric FVIII polypeptide and a second dose of about 25 IU/kg to about 65 IU/kg of the chimeric FVIII polypeptide. 
     
     
         121 . The method of  claim 120 , wherein the dosing interval between the first dose and the second dose is 72 hours to five days. 
     
     
         122 . The method of  claim 111 , wherein the administration resolves greater than 5-20%, greater than 5-15%, greater than 5-10%, greater than 10-20%, or greater than 10-15% of bleeding episode. 
     
     
         123 . The method of  claim 111 , wherein the chimeric FVIII polypeptide is pegylated Factor VIII. 
     
     
         124 . The method of  claim 111 , wherein the FVIII comprises full-length factor VIII, mature factor VIII, or factor VIII with a full or partial deletion of the B domain. 
     
     
         125 . The method of  claim 111 , wherein the chimeric FVIII polypeptide exhibits one or more characteristics selected from:
 (i) wherein a mean clearance (CL) (activity) in the subject is about 2.33±1.08 mL/hour/kg or less;   (ii) wherein a mean residence time (MRT) (activity) in the subject is about 1.5 fold longer than the MRT of a polypeptide consisting of the FVIII;   (iii) wherein a T 1/2  (activity) in the subject is about 1.5 fold longer than the mean T 1/2  (activity) of a polypeptide consisting of the FVIII;   (iv) wherein a mean incremental recovery (K value) in the subject is about 90% of the incremental recovery of a polypeptide consisting of FVIII;   (v) wherein a mean Vss (activity) in the subject is about 37.7 to 79.4 mL/kg;   (vi) wherein a mean AUC/dose (activity) in the subject is about 19.2 *h/dL per IU/kg to 81.71 U*h/dL per IU/kg; and   (vii) a combination thereof.   
     
     
         126 . The method of  claim 111 , wherein each of the multiple doses is about 50 IU/kg or about 65 IU/kg. 
     
     
         127 . The method of  claim 111 , wherein the FcRn BP comprises an Fc or albumin. 
     
     
         128 . A method for prophylactic treatment of a spontaneous bleeding episode in a human subject comprising administering to the subject multiple doses of a chimeric FVIII polypeptide at a dosing interval of about 3 to 7 days between two doses of the chimeric FVIII polypeptide,
 wherein each of the multiple doses is about 25 IU/kg to 65 IU/kg,   wherein the chimeric FVIII polypeptide comprises FVIII and an FcRn BP, and wherein the spontaneous bleeding episode is treated.   
     
     
         129 . The method of  claim 128 , wherein the FVIII comprises full-length factor VIII, mature factor VIII, or factor VIII with a full or partial deletion of the B domain. 
     
     
         130 . The method of  claim 128 , wherein the FcRn BP comprises an Fc or albumin.