초록

Disclosed are compositions and methods related to variant antithrombin III molecules.

대표청구항 ▼

What is claimed is: 1. A variant antithrombin III, comprising a substitution at position P3, wherein the substitution at P3 is an E, H, K, L, P, Q, R, W, or Y. 2. The variant ATIII of claim 1, wherein the variant ATIII has a combined activity greater than or equal to plasma ATIII in a coupled ass

What is claimed is: 1. A variant antithrombin III, comprising a substitution at position P3, wherein the substitution at P3 is an E, H, K, L, P, Q, R, W, or Y. 2. The variant ATIII of claim 1, wherein the variant ATIII has a combined activity greater than or equal to plasma ATIII in a coupled assay. 3. The variant ATIII of claim 2, wherein the ATIII retains base thrombin inhibition activity of at least 5%. 4. The variant ATIII of claim 2, wherein the variant ATIII produce a predicted half life of thrombin at 60 minutes after a bolus administration to a subject that is greater than or equal to 0.9 the half life following a plasma ATIII administration. 5. The variant antithrombin III of claim 2, wherein the variant antithrombin III has an increased protease resistance greater than or equal to the protease resistance of plasma ATIII. 6. The variant antithrombin III of claim 2, wherein the variant antithrombin III has an increased human neutrophil elastase resistance greater than or equal to the protease resistance of plasma ATIII. 7. The variant antithrombin III of claim 2, wherein the variant antithrombin III has an increased cathepsin G resistance greater than or equal to the protease resistance of plasma ATIII. 8. The variant ATIII of claim 1, wherein the variant ATIII retains increased protease resistance and retains observable anti-thrombin activity. 9. The variant ATIII of claim 1, wherein the variant ATIII retains increased protease resistance and retains observable anti factor fXa activity. 10. A method of inhibiting septic disseminated intravascular coagulation in a subject comprising administrating an ATIII variant of claim 1 to a subject having septic disseminated intravascular coagulation, wherein the ATIII variants inhibit thrombin, thereby inhibiting septic disseminated intravascular coagulation in the subject. 11. A method of reducing sepsis in a subject, comprising administering an ATIII variant of claim 1 to a subject having sepsis, thereby reducing sepsis in the subject. 12. A method of inhibiting sepsis induced shock in a subject comprising administering an ATIII variant of claim 1 to a subject, thereby reducing sepsis induced shock in the subject. 13. A method of making the variant ATIII of claim 1, comprising linking in an operative way a nucleic acid molecule encoding a protein set forth in SEQ ID NO:77 wherein the nucleic acid sequence comprises a sequence that hybridizes under stringent hybridization conditions to a sequence set forth SEQ ID NO:79, or a degenerate variant thereof, and a sequence controlling the expression of the nucleic acid. 14. A cell comprising the variant ATIII of claim 1. 15. A cell produced by the process of transforming the cell with any of the disclosed nucleic acids of claim 13. 16. A cell produced by the process of administering the variant ATIII of claim 1.