Coagulation factor XI vaccination: an alternative strategy to prevent thrombosis.
Essentials Coagulation Factor (F) XI is a safe target for the development of antithrombotics. We designed an antigen comprising the human FXI catalytic domain and diphtheria toxin T domain. Antigen immunization reduced plasma FXI activity by 54% and prevented thrombosis in mice. FXI vaccination can serve as an effective strategy for thrombosis prevention.



Background Coagulation factor XI serves as a signal amplifier in the intrinsic coagulation pathway. Blockade of FXI by mAbs or small-molecule inhibitors inhibits thrombosis without causing severe bleeding, which is an inherent risk of currently available antithrombotic agents. Objectives To design an FXI vaccine and assess its efficacy in inhibiting FXI activity and preventing thrombosis. Methods An FXI antigen was generated by fusing the catalytic domain of human FXI to the C-terminus of the transmembrane domain of diphtheria toxin. The anti-FXI antibody response, plasma FXI activity and antithrombotic efficacy in mice immunized with the FXI antigen were examined. Results The antigen elicited a significant antibody response against mouse FXI, and reduced the plasma FXI activity by 54.0% in mice. FXI vaccination markedly reduced the levels of coagulation and inflammation in a mouse model of inferior vena cava stenosis. Significant protective effects were also observed in mouse models of venous thrombosis and pulmonary embolism. Conclusions Our data demonstrate that FXI vaccination can serve as an effective strategy for thrombosis prevention.
State Key Laboratory of Microbial Metabolism and School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
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Zhong
State Key Laboratory of Microbial Metabolism and School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
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Zhang
State Key Laboratory of Microbial Metabolism and School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
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Chen
Shanghai HyCharm Inc., Shanghai, China.
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Deng
State Key Laboratory of Microbial Metabolism and School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China.|Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, Shanghai, China.
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Li
D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D001777:Blood Coagulation / Q000187:drug effects; D020134:Catalytic Domain; D003251:Constriction, Pathologic / Q000473:pathology; D004167:Diphtheria Toxin / Q000737:chemistry; D005172:Factor XI / Q000627:therapeutic use*; D005173:Factor XI Deficiency / Q000097:blood; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010314:Partial Thromboplastin Time; D000072417:Protein Domains; D011517:Prothrombin Time; D011655:Pulmonary Embolism / Q000473:pathology; D013923:Thromboembolism; D013927:Thrombosis / Q000097:blood* / Q000517:prevention & control*; D014612:Vaccines / Q000627:therapeutic use; D014682:Vena Cava, Inferior / Q000473:pathology
D000925:Anticoagulants; D004167:Diphtheria Toxin; D005343:Fibrinolytic Agents; D014612:Vaccines; D005172:Factor XI
antithrombotic; diphtheria toxin; factor XI; inflammation; vaccine