Antidotes for factor XA inhibitors and methods of using the same

摘要

The present invention relates antidotes to anticoagulants targeting factor Xa. The antidotes are factor X and factor Xa protein derivatives that bind to the factor Xa inhibitors thereby substantially neutralizing them but do not assemble into the prothrombinase complex. The derivatives describe herein lack or have reduced intrinsic coagulant activity. Disclosed herein are methods of reversing anticoagulation, stopping or preventing bleeding in a patient that is currently undergoing anticoagulant therapy with a factor Xa inhibitor.

主权项

1. An isolated two-chain polypeptide comprising:
a first chain comprising amino acid residues 95-105 of SEQ ID NO: 20 or a first amino acid sequence having at least 95% sequence identity to amino acid residues 95-105 of SEQ ID NO: 20 and a second chain comprising amino acid residues 112-346 of SEQ ID NO: 20 or a second amino acid sequence having at least 95% sequence identity to amino acid residues 112-346 of SEQ ID NO: 20, wherein the polypeptide (a) has reduced catalytic activity as compared to the corresponding wild-type factor Xa protein, (b) is capable of binding to a factor Xa inhibitor and (c) cannot assemble into a prothrombinase complex, and wherein (i) the first chain does not include amino acid residues 12-50 of SEQ ID NO: 20, (ii) the first chain does not include amino acid residues 51-94 of SEQ ID NO: 20, or (iii) the second chain does not include amino acid residues 347-365 of SEQ ID NO: 6.