Clotting factor-fc chimeric proteins to treat hemophilia

Abstract

The invention relates to a chimeric protein comprising at least one clotting factor and at least a portion of an immunoglobulin constant region. The invention relates to a method of treating a hemostatic disorder comprising administering a therapeutically effective amount of a chimeric protein wherein the chimeric protein comprises at least one clotting factor and at least a portion of an immunoglobulin constant region.

1 .- 58 . (canceled) 
     
     
         59 . A chimeric protein comprising a first polypeptide and a second polypeptide, wherein the first polypeptide comprises
 (i) a clotting factor, which is factor VIII, factor IX, factor XI, factor XII, fibrinogen, prothrombin, factor V, factor VII, factor VIIa, factor X, or factor XIII, and   (ii) at least a portion of an immunoglobulin constant region fused to the clotting factor, which is a neonatal Fc Receptor (FcRn) binding partner, and   the second polypeptide comprises at least a portion of an immunoglobulin constant region,   which is a FcRn binding partner, without the clotting factor of the first polypeptide and without an immunoglobulin variable domain, and   wherein the first polypeptide and the second polypeptide are linked.   
     
     
         60 . The chimeric protein of  claim 59 , wherein the clotting factor is fused to the portion of an immunoglobulin constant region by a linker. 
     
     
         61 . The chimeric protein of  claim 60 , wherein the linker comprises about 1 to about 20 amino acids. 
     
     
         62 . The chimeric protein of  claim 59 , wherein the portion of an immunoglobulin constant region of the first polypeptide is an Fc fragment. 
     
     
         63 . The chimeric protein of  claim 62 , wherein the portion of an immunoglobulin constant region of the second polypeptide is an Fc fragment. 
     
     
         64 . The chimeric protein of  claim 59 , wherein the portion of an immunoglobulin constant region of the first polypeptide and the portion of an immunoglobulin constant region of the second polypeptide are identical. 
     
     
         65 . The chimeric protein of  claim 59 , wherein the clotting factor is full-length factor VIII or B-domain deleted factor VIII. 
     
     
         66 . The chimeric protein of  claim 59 , wherein the clotting factor is factor IX. 
     
     
         67 . The chimeric protein of  claim 59 , wherein the clotting factor is factor VII or factor VIIa. 
     
     
         68 . A pharmaceutical composition comprising the chimeric protein of  claim 59  and a pharmaceutically acceptable carrier. 
     
     
         69 . The composition of  claim 68 , which is formulated for administering intravenously, subcutaneously, intra-muscularly, orally, sublingually, buccally, nasally, rectally, vaginally or via a pulmonary route. 
     
     
         70 . The composition of  claim 68 , further comprising at least one agent, which is capable of treating a disease or condition. 
     
     
         71 . The composition of  claim 70 , wherein the at least one agent is a protein comprising a clotting factor. 
     
     
         72 . A nucleic acid molecule encoding a chimeric protein comprising a first polypeptide and a second polypeptide, the nucleic acid molecule comprising:
 (i) a first nucleic acid sequence encoding the first polypeptide, which comprises a clotting factor and at least a portion of an immunoglobulin constant region, which is a neonatal Fc Receptor (FcRn) binding partner, wherein the clotting factor is factor VIII, factor IX, factor XI, factor XII, fibrinogen, prothrombin, factor V, factor VII, factor VIIa, factor X, or factor XIII; and   (ii) a second nucleic acid sequence encoding the second polypeptide, which comprises at least a portion of an immunoglobulin constant region, which is a FcRn binding partner, wherein the second nucleic acid sequence does not encode the clotting factor.   
     
     
         73 . A vector comprising the nucleic acid molecule of  claim 72 . 
     
     
         74 . A host cell comprising the vector of  claim 73 . 
     
     
         75 . A method of making a chimeric protein having clotting activity comprising:
 a) transfecting a cell comprising the nucleic acid molecule of  claim 72 ; and   b) culturing the cell in media under conditions such that the chimeric protein is expressed.   
     
     
         76 . A method of treating a hemostatic disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a chimeric protein, which comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises
 (i) a clotting factor, which is factor VIII, factor IX, factor XI, factor XII, fibrinogen, prothrombin, factor V, factor VII, factor VIIa, factor X, or factor XIII, and   (ii) at least a portion of an immunoglobulin constant region fused to the clotting factor, which is a FcRn binding partner, and   the second polypeptide comprises at least a portion of an immunoglobulin constant region,   which is a FcRn binding partner, without the clotting factor of the first polypeptide and without an immunoglobulin variable domain, and   wherein the first polypeptide and the second polypeptide are linked.   
     
     
         77 . The method of  claim 76 , wherein the chimeric protein treats an acute bleeding episode in the subject. 
     
     
         78 . The method of  claim 77 , wherein the chimeric protein is administered intravenously, subcutaneously, intra-muscularly, orally, sublingually, buccally, nasally, rectally, vaginally or via a pulmonary route.