Von willebrand factor- and factor VIII-polymer conjugates having a releasable linkage

摘要

The present invention provides von Willebrand Factor-polymer conjugates and Factor VIII-polymer conjugates, each having a releasable linkage. Methods of making conjugates, methods for administering conjugates, are also provided.

主权项

1. A method of treating a bleeding disorder in a subject, said method comprising administering a therapeutically effective amount of a modified protein having an extended in-vivo half life over the unmodified parent protein, wherein the unmodified parent protein is either a von Willebrand Factor moiety or a Factor VIII moiety and the modified protein is a conjugate having a formula:wherein:
POLY1 is a first water-soluble polymer; POLY2 is a second water-soluble polymer; X1 is a first spacer moiety; X2 is a second spacer moiety; Hα is an ionizable hydrogen atom; R1 is H or an organic radical; R2 is H or an organic radical; (a) is either zero or one; (b) is either zero or one; Re1, when present, is a first electron altering group; Re2, when present, is a second electron altering group; Y1 is O or S; and Y2 is O or S, such thatfrom the formula is a releasable linkage that is selected from a carbamate linkage, a thiocarbamate linkage, and a dithiocarbamate linkage; and
(vWF/F8) is a residue of an amine-containing biologically active agent that is either a von Willebrand Factor moiety or a Factor VIII moiety.