Method for increasing the serum half-life of a biologically active molecule
AssigneeChiron Corporation
InventorsRobert J. Drummond, Steve Rosenberg
Life of this patent
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Abstract
A method is provided for preparing a biologically active molecule having an increased serum half-life. The method involves conjugating a polymer such as polyethylene glycol to the biologically active molecule. Also provided are polypeptide drugs having an increased serum half-life, e.g., human urokinase plasminogen activator (human “uPA” or “hUPA”) or a fragment or derivative thereof. Pharmaceutical compositions containing such molecules and methods of using them to treat uPA-mediated and uPA receptor-mediated disorders are also provided.
Claims13
A method for conjugating urokinase plasminogen activator1-48 having adjacent amino and alcohol groups at the N-terminus thereof to polyethylene glycol in the form of polyethylene glycol hydrazide or semicarbazide, comprising:
- (a) oxidatively cleaving between the adjacent amino and alcohol groups to yield an aldehyde functionality in place thereof, and
- (b) reacting the aldehyde-containing urokinase plasminogen activator1-48 provided in step (a) with the polyethylene glycol hydrazide or semicarbazide under reaction conditions effective to promote formation of PEGylated polypeptide, wherein the polypeptide is bound to polyethylene glycol through a hydrazone or semicarbazone linkage.
A modified polypeptide comprising a biologically active polypeptidc selected from the group consisting of urokinasc plasminogen activator1-48 and active portions thereof, conjugated to polyethylene glycol through a hydrazone or semicarbazone linkage, wherein said modified polypeptide exhibits a proportional increase in serum half-life in an individual which is greater than any proportional decrease in its biological activity, relative to unmodified urokinase plasminogen activator1-48.
A method for increasing the serum half-life of a polypeptide selected from the group consisting of urokinase plasminogen activator1-48 and active portions thereof, comprising:
- treating the polypeptide with a reagent effective to generate an N-terninal aldehyde;
- and coupling the polypeptide to activated polyethylene glycol (PEG) selected from the group consisting of polyethylene glycol hydrazide and polyethylene glycol semicarbazide under reaction conditions effective to promote formation of a PEG-conjugated polypeptide.
Dependencies are inferred from the claim text.