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 VIIIa, Factor IX, Factor IXa, Factor VII, or Factor VIIa, 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 60 , wherein the linker comprises the sequence (GlyGlySer)n or SEQ ID NO: 31, wherein n is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. 
     
     
         63 . The chimeric protein of  claim 59 , wherein the portion of an immunoglobulin constant region of the first polypeptide is an Fc fragment. 
     
     
         64 . The chimeric protein of  claim 63 , wherein the portion of an immunoglobulin constant region of the second polypeptide is an Fc fragment. 
     
     
         65 . The chimeric protein of  claim 63 , wherein the Fc fragment comprises an amino acid sequence having at least 80% identity with the sequence set forth in SEQ ID NO: 3, wherein the amino acid sequence binds to FcRn. 
     
     
         66 . The chimeric protein of  claim 64 , wherein the Fc fragment comprises an amino acid sequence having at least 80% identity with the sequence set forth in SEQ ID NO: 3, wherein the amino acid sequence binds to FcRn. 
     
     
         67 . 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. 
     
     
         68 . The chimeric protein of  claim 59 , wherein the first polypeptide and the second polypeptide are linked covalently or non-covalently. 
     
     
         69 . The chimeric protein of  claim 59 , wherein the first polypeptide and the second polypeptide are linked via a disulfide bond. 
     
     
         70 . The chimeric protein of  claim 59 , wherein the second polypeptide consists of at least a portion of an immunoglobulin constant region comprising a FcRn binding partner. 
     
     
         71 . The chimeric protein of  claim 59 , wherein the clotting factor is full-length Factor VIII or B-domain deleted Factor VIII. 
     
     
         72 . The chimeric protein of  claim 59 , wherein the clotting factor is Factor IX or Factor IXa. 
     
     
         73 . The chimeric protein of  claim 59 , wherein the clotting factor is Factor VII or Factor VIIa. 
     
     
         74 . A pharmaceutical composition comprising the chimeric protein of  claim 59  and a pharmaceutically acceptable carrier. 
     
     
         75 . The composition of  claim 74 , which promotes hemostasis. 
     
     
         76 . The composition of  claim 75 , which is formulated for administering intravenously, subcutaneously, intra-muscularly, orally, sublingually, buccally, nasally, rectally, vaginally or via a pulmonary route. 
     
     
         77 . The composition of  claim 74 , further comprising at least one agent, which is capable of treating a disease or condition. 
     
     
         78 . The composition of  claim 77 , wherein the at least one agent is a protein comprising a clotting factor. 
     
     
         79 . 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 VIIIa, Factor IX, Factor IXa, Factor VII, or Factor VIIa; 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.   
     
     
         80 . A vector comprising the nucleic acid molecule of  claim 79 . 
     
     
         81 . A host cell comprising the vector of  claim 80 . 
     
     
         82 . A method of making a chimeric protein having clotting activity comprising:
 a) transfecting a cell comprising the nucleic acid molecule of  claim 79 ; and   b) culturing the cell in media under conditions such that the chimeric protein is expressed.   
     
     
         83 . 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 VIIIa, Factor IX, Factor IXa, Factor VII, or Factor VIIa, 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.   
     
     
         84 . The method of  claim 83 , wherein the chimeric protein treats an acute bleeding episode in the subject. 
     
     
         85 . The method of  claim 84 , wherein the chimeric protein is administered intravenously, subcutaneously, intra-muscularly, orally, sublingually, buccally, nasally, rectally, vaginally or via a pulmonary route.