Polymer-von Willebrand factor-conjugates
AssigneesBaxter International Inc., Baxter Healthcare S.A.
InventorsFriedrich Scheiflinger, Peter Turecek, Juergen Siekmann
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Abstract
The present invention relates to a proteinaceous construct (also designated as polymer-VWF-conjugate) comprising plasmatic and/or recombinant von Willebrand factor (VWF), said VWF being bound to at least one physiologically acceptable polymer molecule, as well as to a complex between said proteinaceous construct and at least one factor VIII (FVIII) protein. The physiologically acceptable polymer molecule can be, for instance, polyethylene glycol (PEG) or polysialic acid (PSA). Further the present invention relates to methods for prolonging the in vivo-half-life of VWF or FVIII in the blood of a mammal having a bleeding disorder associated with functional defects of or deficiencies of at least one of FVIII or VWF.
Claims13
A method for forming a proteinaceous molecule comprising a von Willebrand Factor (VWF) molecule and a PEG moiety covalently bound to at least one carbohydrate residue on said VWF molecule, said proteinaceous molecule having the capability of binding at least one Factor VIII (FVIII) molecule, comprising:
- a) providing a VWF molecule selected from the group consisting of plasmatic VWF, recombinant VWF, and dimers and multimers thereof;
- b) oxidizing carbohydrate residues on said VWF molecule;
- c) contacting said carbohydrate residues with a PEG reagent containing a hydrazide group;
- and d) allowing said PEG hydrazide reagent to covalently bind to at least one carbohydrate residue on said VWF, thereby forming said proteinaceous molecule, wherein the in vivo half-life of said proteinaceous molecule is increased as compared to the in vivo half-life of a VWF molecule and the in vivo half-life of said FVIII molecule bound to said proteinaceous molecule is increased as compared to the in vivo half-life of a FVIII molecule not bound to said proteinaceous molecule.
A method for forming a proteinaceous construct molecule comprising a von Willebrand Factor (VWF) molecule and a polysialic acid (PSA) moiety covalently bound to at least one lysine residue on said VWF molecule, said proteinaceous molecule having the capability of binding at least one Factor VIII (FVIII) molecule, comprising:
- a) providing a VWF molecule selected from the group consisting of plasmatic VWF, recombinant VWF, and dimers and multimers thereof;
- b) contacting said VWF molecule with a PSA reagent containing an aldehyde;
- c) allowing said PSA reagent to covalently bind to at least one lysine residue on said VWF to form a Schiff base in solution;
- and d) contacting said solution with a reducing agent to form a secondary amino bond;
- thereby forming said proteinaceous molecule, wherein the in vivo half-life of said proteinaceous molecule is increased as compared to the in vivo half-life of a VWF molecule and the in vivo half-life of said FVIII molecule bound to said proteinaceous molecule is increased as compared to the in vivo half-life of a FVIII molecule not bound to said proteinaceous molecule.
A method for forming a proteinaceous construct molecule comprising a von Willebrand Factor (VWF) molecule and a hyaluronic acid (HA) moiety covalently bound to at least one lysine residue on said VWF molecule, said proteinaceous molecule having the capability of binding at least one Factor VIII (FVIII) molecule, comprising:
- a) providing a VWF molecule selected from the group consisting of plasmatic VWF, recombinant VWF, and dimers and multimers thereof;
- b) contacting a solution of HA with an oxidizing agent to form activated HA;
- c) contacting said VWF molecule with said activated HA, thereby forming said proteinaceous molecule, wherein the in vivo half-life of said proteinaceous molecule is increased as compared to the in vivo half-life of a VWF molecule and the in vivo half-life of said FVIII molecule bound to said proteinaceous molecule is increased as compared to the in vivo half-life of a FVIII molecule not bound to said proteinaceous molecule.
Dependencies are inferred from the claim text.