Chimeric clotting factors

Abstract

Chimeric clotting factors which localize the therapeutic to sites of coagulation (e.g., by being targeted to platelets or being activatable at sites of coagulation), have reduced clearance rates, have improved manufacturability, have reduced thrombogenicity, have enhanced activity, or have more than one of these characteristics are described as are methods for making chimeric clotting factors and methods for improving hemostasis using these clotting factors.

1 . A chimeric clotting factor which comprises i) a clotting factor selected from the group consisting of FVII, FIX and FX and ii) a targeting moiety and, optionally, iii) a spacer moiety between the clotting factor and the targeting moiety. 
     
     
         2 . The chimeric clotting factor of  claim 1 , which comprises a structure represented by the formula A B C, wherein A is the clotting factor; wherein B is a spacer moiety; and wherein C is at least one targeting moiety which binds to platelets. 
     
     
         3 - 4 . (canceled) 
     
     
         5 . The chimeric clotting factor of  claim 1 , further comprising a scaffold moiety and, optionally, a second spacer moiety. 
     
     
         6 . (canceled) 
     
     
         7 . The chimeric clotting factor of  claim 1 , further comprising a dimeric Fc region comprising a first Fc moiety, F1 and a second Fc moiety, F2. 
     
     
         8 . The chimeric clotting factor of  claim 7 , wherein the chimeric clotting factor is expressed as a polypeptide comprising a cleavable single chain Fc (cscFc) linker interposed between the two Fc moieties, wherein the cscFc linker is adjacent to at least one enzymatic cleavage site which results in cleavage of the cscFc polypeptide linker. 
     
     
         9 - 19 . (canceled) 
     
     
         20 . The chimeric clotting factor of  claim 7 , wherein the targeting moiety is fused to at least one of F1 and F2. 
     
     
         21 - 23 . (canceled) 
     
     
         24 . The chimeric clotting factor of  claim 1 , wherein the targeting moiety is selected from the group consisting of: an antibody molecule, an antigen binding fragment of an antibody molecule, an scFv molecule, a receptor binding portion of a receptor, and a peptide. 
     
     
         25 - 31 . (canceled) 
     
     
         32 . The chimeric clotting factor of  claim 1 , wherein the clotting factor is Factor VII. 
     
     
         33 . (canceled) 
     
     
         34 . The chimeric clotting factor of  claim 1 , wherein the clotting factor is Factor IX. 
     
     
         35 . (canceled) 
     
     
         36 . The chimeric clotting factor of  claim 1 , wherein the clotting factor is Factor X. 
     
     
         37 - 39 . (canceled) 
     
     
         40 . The chimeric clotting factor of  claim 1 , wherein the chimeric clotting factor comprises a heterologous enzymatic cleavage site not naturally present in the clotting factor. 
     
     
         41 - 43 . (canceled) 
     
     
         44 . A polypeptide comprising FVII, which FVII comprises a heterologous enzymatic cleavage site activatable by a component of the clotting cascade. 
     
     
         45 . The polypeptide of  claim 44 , wherein the polypeptide comprises a scaffold moiety and, optionally, a spacer moiety. 
     
     
         46 . The chimeric clotting factor of  claim 45 , wherein the scaffold moiety is a dimeric Fc region comprising a first Fc moiety, F1 and a second Fc moiety, F2. 
     
     
         47 - 70 . (canceled) 
     
     
         71 . A nucleic acid molecule encoding a chimeric clotting factor of  claim 1 . 
     
     
         72 . A vector comprising the nucleic acid molecule of  claim 71 . 
     
     
         73 - 74 . (canceled) 
     
     
         75 . A host cell comprising the vector of  claim 72 , wherein the host cell expresses an enzyme capable of intracellular processing. 
     
     
         76 - 77 . (canceled) 
     
     
         78 . A method for producing a chimeric clotting factor comprising culturing the host cell of  claim 75  in culture and recovering the chimeric clotting factor from the medium. 
     
     
         79 . A processed, heterodimeric polypeptide comprising two polypeptide chains, wherein said processed, heterodimeric polypeptide is made by expressing the vector of  claim 78  in a cell cultured in cell culture medium and isolating the mature, heterodimeric polypeptide from the culture medium. 
     
     
         80 . A pharmaceutical composition comprising the chimeric clotting factor  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         81 . (canceled) 
     
     
         82 . A method for improving hemostasis in a subject, comprising administering to a subject in need thereof an effective amount of the composition of  claim 1 .