ANTIDOTES FOR FACTOR XA INHIBITORS AND METHODS OF USING THE SAME
The present invention relates antidotes to anticoagulants targeting factor Xa. The antidoes are 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 stopping or preventing bleeding in a patient that is currently undergoing anticoagulant therapy with a factor Xa inhibitor.
1 . A molecule comprising a two-chain polypeptide coupled to an immunoglobin Fc fragment,
wherein the two-chain polypeptide comprises (a) a first chain comprising the amino acid sequence of SEQ ID NO: 14 or a first amino acid sequence having at least 95% sequence identity to SEQ ID NO: 14, and (b) a second chain comprising the amino acid sequence of SEQ ID NO: 15 or a second amino acid sequence having at least 95% sequence identity to SEQ ID NO: 15, and
wherein the polypeptide (1) has reduced catalytic activity as compared to the wild-type factor Xa protein, (2) is capable of binding to a factor Xa inhibitor and (3) cannot assemble into a prothrombinase complex.
2 . The molecule of claim 1 , wherein the first chain comprises the amino acid sequence of SEQ ID NO: 14 and the second chain comprises the amino acid sequence of SEQ ID NO: 15.
3 . The molecule of claim 2 , which is a chimeric protein that comprises the two-chain polypeptide and the Fc fragment.
4 . The molecule of claim 3 , wherein the Fc fragment is an IgG1 Fc fragment.
5 . The molecule of claim 2 , wherein the two-chain polypeptide is coupled to the Fc fragment through a disulfide bond.
6 . A pharmaceutical composition comprising a carrier and the molecule of claim 1 .
7 . A method for reversing anticoagulation in a subject undergoing anticoagulant therapy with a factor Xa inhibitor, comprising administering to the subject an effective amount of the composition of claim 6 .
8 . The method of claim 7 , wherein the factor Xa inhibitor is selected from the group consisting of fondaparinux, idraparinux, biotinylated idraparinux, enoxaparin, fragmin, NAP-5, rNAPc2, tissue factor pathway inhibitor, DX-9065a, YM-60828, YM-150, apixaban, rivaroxaban, PD-348292, otamixaban, DU-176b, LY517717, GSK913893, razaxaban, low molecular weight heparin, betrixaban or a pharmaceutically acceptable salt thereof, and combinations thereof.