Factor VIIa-polysialic acid conjugates having prolonged in vivo half-life
View Patent ↗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 chemically-modified proteinaceous construct comprising,
(a) an activated factor VII (FVIIa) molecule which is plasmatic FVIIa or recombinant FVIIa (rFVIIa); 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 chemically-modified.
2. The chemically-modified 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 chemically-modified.
3. The chemically-modified 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 chemically-modified.
4. The chemically-modified 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 chemically-modified 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 chemically-modified proteinaceous construct of claim 1 , wherein said physiologically acceptable carbohydrate moiety is a polysialic acid.
7. A pharmaceutical composition comprising an effective amount of the chemically-modified 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 chemically-modified proteinaceous construct of claim 1 .
9. A method of controlling bleeding in a mammal during surgery or trauma, said method comprising administering the chemically-modified proteinaceous construct of claim 1 .
10. A kit comprising an effective amount of the chemically-modified 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.