Factor IX Polypeptides and Methods of Use Thereof

Abstract

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

1 - 121 . (canceled) 
     
     
         122 . A method of treating hemophilia B in a human subject in need thereof, comprising administering to the subject a dose of at least about 10 IU/kg of a chimeric Factor IX (FIX) polypeptide, comprising FIX and an FcRn binding partner (FcRn BP), at a dosing interval of a week or longer. 
     
     
         123 . The method of  claim 122 , wherein the subject exhibits a plasma FIX activity above 1 IU/dL during the dosing interval. 
     
     
         124 . The method of  claim 122 , wherein the subject exhibits a baseline-subtracted plasma FIX activity trough level of at least 1 IU/dL, and wherein the baseline is the lowest measured plasma FIX level in the subject prior to administering the first dose of the chimeric FIX polypeptide. 
     
     
         125 . The method of  claim 122 , wherein the long-acting FIX polypeptide exhibits one or more characteristics selected from the group consisting of:
 a. an incremental recovery (K-Value) (activity; observed) greater than 0.75 IU/dL per IU/kg;   b. an incremental recovery (K value) (activity; observed) of about 0.62-1.17 IU/dL per IU/kg;   c. a clearance (CL) (activity) of about 1.84-4.58 mL/hour/kg;   d. a clearance (CL) (activity) of about 3.36±0.93 mL/hour/kg;   e. a mean residence time (MRT) (activity) of about 53.1-85.8 hours;   f. a mean residence time (MRT) (activity) of about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, or about 90 hours;   g. a MRT (activity) of at least about 68.05±11.16 hours;   h. a t1/2beta (activity) of about 40-67.4 hours;   i. a t1/2beta (activity) of at least about 40, about 45, about 50, about 55, about 60, about 65, about 70, or about 75 hours;   j. a t1/2beta (activity) of at least 75 hours;   k. a t1/2beta (activity) of about 3 fold longer than the t1/2beta (activity) of a polypeptide consisting of FIX;   l. a Vss (activity) of about 145-365 mL/kg;   m. a Vss (activity) of about 226±67.76 mL/kg;   n. an AUC/dose of about 21.80-54.30 IU*h/dL per IU/kg; and   o. an AUC/dose of about 32.44±10.75 IU*h/dL per IU/kg.   
     
     
         126 . The method of  claim 122 , wherein the dosing interval is about 6 to about 10 days between two doses. 
     
     
         127 . The method of  claim 126 , wherein the dose is selected from the group consisting of about 10 IU/kg, about 15 IU/kg, about 20 IU/kg, about 25 IU/kg, about 30 IU/kg, about 35 IU/kg, about 40 IU/kg, about 45 IU/kg, about 50 IU/kg, about 55 IU/kg, about 60 IU/kg, about 65 IU/kg, about 70 IU/kg, about 75 IU/kg, about 80 IU/kg, about 85 IU/kg, about 90 IU/kg, about 95 IU/kg, about 100 IU/kg, about 105 IU/kg, and about 110 IU/kg. 
     
     
         128 . The method of  claim 127 , wherein the dosing interval is selected from the group consisting of about 6 days, about 7 days, about 8 days, about 9 days, and about 10 days. 
     
     
         129 . The method of  claim 122 , wherein the dosing interval is about 9 days to about 18 days. 
     
     
         130 . The method of  claim 129 , wherein the dose is selected from the group consisting of about 90 IU/kg, about 95 IU/kg, about 100 IU/kg, about 105 IU/kg, about 110 IU/kg, about 115 IU/kg, about 120 IU/kg, about 125 IU/kg, about 130 IU/kg, about 135 IU/kg, about 140 IU/kg, about 145 IU/kg, about 150 IU/kg, about 155 IU/kg, about 160 IU/kg, about 165 IU/kg, about 170 IU/kg, about 175 IU/kg, and about 180 IU/kg. 
     
     
         131 . The method of  claim 130 , wherein the dosing interval is selected from the group consisting of about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, and about 18 days. 
     
     
         132 . The method of  claim 122 , wherein the FcRn BP comprises an Fc or albumin, or a fragment thereof. 
     
     
         133 . The method of  claim 132 , wherein the FIX comprises amino acids 1 to 415 of SEQ ID NO: 2. 
     
     
         134 . The method of  claim 132 , wherein the Fc comprises amino acids 1 to 227 of SEQ ID NO: 4. 
     
     
         135 . The method of  claim 122 , wherein the chimeric FIX polypeptide is a hybrid and comprises a second polypeptide, which comprises an additional FcRn BP associated with the first FcRn BP. 
     
     
         136 . The method of  claim 122 , wherein the dose is administered intravenously or subcutaneously. 
     
     
         137 . A chimeric FIX polypeptide comprising FIX and an FcRn BP, wherein the chimeric FIX polypeptide has greatly reduced phosphorylation and sulfation in comparison to plasma derived Factor IX. 
     
     
         138 . The polypeptide of  claim 137 , wherein less than about 25% of the FIX is phosphorylated and less than about 25% of the FIX is sulfated. 
     
     
         139 . The polypeptide of  claim 137 , wherein less than about 10% of the FIX is phosphorylated and less than about 9% of the FIX is sulfated. 
     
     
         140 . A polynucleotide encoding the polypeptide of  claim 137 . 
     
     
         141 . A host cell comprising the polynucleotide of  claim 140 .