FACTOR VIIA-POLYSIALIC ACID CONJUGATES HAVING PROLONGED IN VIVO HALF-LIFE
The present invention relates to a proteinaceous construct comprising plasmatic or recombinant factor VIIa (FVIIa) or biologically active derivatives thereof, which are bound to a carbohydrate moiety comprising 1-4 sialic acid units, wherein the in vivo half-life of the proteinaceous construct is substantially prolonged in the blood of a mammal, as compared to the in vivo half-life of a FVIIa molecule not bound to a carbohydrate moiety. The invention also provides a method for controlling bleeding in a mammal having a bleeding disorder due to functional defects or deficiencies of FVIIa, FVIII, or FIX. The invention also provides a method for controlling bleeding in a mammal during surgery or trauma.
1 . A proteinaceous construct comprising,
(a) an activated factor VII (FVIIa) molecule selected from the group consisting of plasmatic FVIIa, recombinant FVIIa (rFVIIa), and a biologically active derivative of FVIIa; and
(b) at least one physiologically acceptable carbohydrate moiety comprising 1-4 sialic acid units bound to said FVIIa molecule;
wherein the in vivo half-life of said construct is prolonged in the blood of a mammal as compared to the in vivo half-life of a FVIIa molecule that is not bound to said carbohydrate moiety.
2 . The proteinaceous construct of claim 1 wherein the in vivo half-life of said construct is increased by at least a factor of about two as compared to the in vivo half-life of a FVIIa molecule that is not bound to said carbohydrate moiety.
3 . The proteinaceous construct of claim 1 wherein the in vivo half-life of said construct is increased by at least a factor of about three as compared to the in vivo half-life of a FVIIa molecule that is not bound to said carbohydrate moiety.
4 . The proteinaceous construct of claim 1 , wherein the physiologically acceptable carbohydrate moiety is directly covalently linked to at least one amino acid residue of said FVIIa molecule.
5 . The proteinaceous construct of claim 1 , wherein the physiologically acceptable carbohydrate moiety is non-covalently linked to at least one amino acid residue of said FVIIa molecule.
6 . The proteinaceous construct of claim 1 , wherein said physiologically acceptable carbohydrate moiety is a polysialic acid or a derivative thereof.
7 . A pharmaceutical composition comprising an effective amount of the proteinaceous construct of claim 1 , and one or more compounds selected from the group consisting of a pharmaceutically acceptable carrier, diluent, salt, buffer, and excipient.
8 . A method of controlling bleeding in a mammal having a bleeding disorder associated with functional defects or deficiencies of at least one of FVIIa, factor VIII (FVIII) and factor IX (FIX), said method comprising administering the proteinaceous construct of claim 1 .
9 . A method of controlling bleeding in a mammal during surgery or trauma, said method comprising administering the proteinaceous construct of claim 1 .
10 . A kit comprising a an effective amount of the proteinaceous construct of claim 1 , packaged in a container, said kit optionally containing a second therapeutic agent, and further comprising a label attached to or packaged with the container, the label describing the contents of the container and providing indications and/or instructions regarding use of the contents of the container for controlling bleeding in a mammal.
11 . The kit of claim 10 wherein the container is a vial or bottle or prefilled syringe.