Engineering and evaluation of FXa bypassing agents that restore hemostasis following Apixaban associated bleeding

Jankowski, Wojciech; Surov, Stepan S.; Hernandez, Nancy E.; Rawal, Atul; Battistel, Marcos; Freedberg, Daron; Ovanesov, Mikhail V.; Sauna, Zuben E.

doi:10.1038/s41467-024-48278-1

Title: Engineering and evaluation of FXa bypassing agents that restore hemostasis following Apixaban associated bleeding

Journal Article · 09 May 2024 · Nature Communications

DOI: https://doi.org/10.1038/s41467-024-48278-1 · OSTI ID:2471331

^[1];

^[1]; Battistel, Marcos ^[1];

^[1]; Ovanesov, Mikhail V. ^[1];

^[1]

US Food and Drug Administration (USFDA), Silver Spring, MD (United States). Center for Biologics Evaluation and Research

Direct oral anticoagulants (DOACs) targeting activated factor Xa (FXa) are used to prevent or treat thromboembolic disorders. DOACs reversibly bind to FXa and inhibit its enzymatic activity. However, DOAC treatment carries the risk of anticoagulant-associated bleeding. Currently, only one specific agent, andexanet alfa, is approved to reverse the anticoagulant effects of FXa-targeting DOACs (FXaDOACs) and control life-threatening bleeding. However, because of its mechanism of action, andexanet alfa requires a cumbersome dosing schedule, and its use is associated with the risk of thrombosis. Here, we present the computational design, engineering, and evaluation of FXa-variants that exhibit anticoagulation reversal activity in the presence of FXaDOACs. Our designs demonstrate low DOAC binding affinity, retain FXa-enzymatic activity and reduce the DOAC-associated bleeding by restoring hemostasis in mice treated with apixaban. Importantly, the FXaDOACs reversal agents we designed, unlike andexanet alfa, do not inhibit TFPI, and consequently, may have a safer thrombogenic profile.

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Research Organization:: Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC); USFDA

Grant/Contract Number:: SC0014664

OSTI ID:: 2471331

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 15; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Title: Engineering and evaluation of FXa bypassing agents that restore hemostasis following Apixaban associated bleeding

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