Development of Coagulation Factor XII Antibodies for Inhibiting Vascular Device-Related Thrombosis

Overview

Journal Cell Mol Bioeng

Publisher Springer

Specialty Biomedical Engineering

Date 2021 Apr 19

PMID 33868498

Citations 12

Authors

T C L Kohs

C U Lorentz

J Johnson

C Puy

S R Olson

J J Shatzel

D Gailani

M T Hinds

E I Tucker

A Gruber

O J T McCarty

M Wallisch

Affiliations

Soon will be listed here.

Abstract

Introduction: Vascular devices such as stents, hemodialyzers, and membrane oxygenators can activate blood coagulation and often require the use of systemic anticoagulants to selectively prevent intravascular thrombotic/embolic events or extracorporeal device failure. Coagulation factor (F)XII of the contact activation system has been shown to play an important role in initiating vascular device surface-initiated thrombus formation. As FXII is dispensable for hemostasis, targeting the contact activation system holds promise as a significantly safer strategy than traditional antithrombotics for preventing vascular device-associated thrombosis.

Objective: Generate and characterize anti-FXII monoclonal antibodies that inhibit FXII activation or activity.

Methods: Monoclonal antibodies against FXII were generated in FXII-deficient mice and evaluated for their binding and anticoagulant properties in purified and plasma systems, in whole blood flow-based assays, and in an non-human primate model of vascular device-initiated thrombus formation.

Results: A FXII antibody screen identified over 400 candidates, which were evaluated in binding studies and clotting assays. One non-inhibitor and six inhibitor antibodies were selected for characterization in functional assays. The most potent inhibitory antibody, 1B2, was found to prolong clotting times, inhibit fibrin generation on collagen under shear, and inhibit platelet deposition and fibrin formation in an extracorporeal membrane oxygenator deployed in a non-human primate.

Conclusion: Selective contact activation inhibitors hold potential as useful tools for research applications as well as safe and effective inhibitors of vascular device-related thrombosis.

Citing Articles

Discovery of a new lead molecule to develop a novel class of human factor XIIa inhibitors.

Dumas A, Goyal N, Mottamal M, Afosah D, Al-Horani R J Thromb Thrombolysis. 2024; 57(8):1308-1314.

PMID: 39487279 DOI: 10.1007/s11239-024-03054-2.

Pharmacologic targeting of coagulation factors XII and XI by monoclonal antibodies reduces thrombosis in nitinol stents under flow.

Keeling N, Wallisch M, Johnson J, Le H, Vu H, Jordan K J Thromb Haemost. 2024; 22(5):1433-1446.

PMID: 38331196 PMC: 11055672. DOI: 10.1016/j.jtha.2024.01.023.

Factor XI as a therapeutic target in neuroinflammatory disease.

Taskin B, Kohs T, Shatzel J, Puy C, McCarty O Curr Opin Hematol. 2023; 31(1):32-38.

PMID: 37694771 PMC: 10843631. DOI: 10.1097/MOH.0000000000000787.

Factor XII Structure-Function Relationships.

Shamanaev A, Litvak M, Ivanov I, Srivastava P, Sun M, Dickeson S Semin Thromb Hemost. 2023; 50(7):937-952.

PMID: 37276883 PMC: 10696136. DOI: 10.1055/s-0043-1769509.

Targeting the Contact Pathway of Coagulation for the Prevention and Management of Medical Device-Associated Thrombosis.

Goel A, Tathireddy H, Wang S, Vu H, Puy C, Hinds M Semin Thromb Hemost. 2023; 50(7):989-997.

PMID: 37044117 PMC: 11069398. DOI: 10.1055/s-0043-57011.

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