A single-domain antibody targeting factor XII inhibits both thrombosis and inflammation

Pengfei Xu, Yingjie Zhang, Junyan Guo, Huihui Li, Sandra Konrath, Peng Zhou, Liming Cai, Haojie Rao, Hong Chen, Jian Lin, Zhao Cui, Bingyang Ji, Jianwei Wang, Nailin Li, Liu De-Pei, Thomas Renné and Miao Wang ()
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Pengfei Xu: Chinese Academy of Medical Sciences and Peking Union Medical College
Yingjie Zhang: Chinese Academy of Medical Sciences and Peking Union Medical College
Junyan Guo: Chinese Academy of Medical Sciences and Peking Union Medical College
Huihui Li: Chinese Academy of Medical Sciences and Peking Union Medical College
Sandra Konrath: University Medical Center Hamburg-Eppendorf (UKE)
Peng Zhou: Peking University
Liming Cai: Chinese Academy of Medical Sciences and Peking Union Medical College
Haojie Rao: Chinese Academy of Medical Sciences and Peking Union Medical College
Hong Chen: Chinese Academy of Medical Sciences and Peking Union Medical College
Jian Lin: Peking University
Zhao Cui: Peking University First Hospital
Bingyang Ji: Chinese Academy of Medical Sciences and Peking Union Medical College
Jianwei Wang: Chinese Academy of Medical Sciences and Peking Union Medical College
Nailin Li: Karolinska Institute
Liu De-Pei: Chinese Academy of Medical Sciences & Peking Union Medical College
Thomas Renné: University Medical Center Hamburg-Eppendorf (UKE)
Miao Wang: Chinese Academy of Medical Sciences and Peking Union Medical College

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Factor XII (FXII) is the zymogen of the plasma protease FXIIa that activates the intrinsic coagulation pathway and the kallikrein kinin-system. The role of FXII in inflammation has been obscure. Here, we report a single-domain antibody (nanobody, Nb) fused to the Fc region of a human immunoglobulin (Nb-Fc) that recognizes FXII in a conformation-dependent manner and interferes with FXIIa formation. Nb-Fc treatment inhibited arterial thrombosis in male mice without affecting hemostasis. In a mouse model of extracorporeal membrane oxygenation (ECMO), FXII inhibition or knockout reduced thrombus deposition on oxygenator membranes and systemic microvascular thrombi. ECMO increased circulating levels of D-dimer, alkaline phosphatase, creatinine and TNF-α and triggered microvascular neutrophil adherence, platelet aggregation and their interaction, which were substantially attenuated by FXII blockade. Both Nb-Fc treatment and FXII knockout markedly ameliorated immune complex-induced local vasculitis and anti-neutrophil cytoplasmic antibody-induced systemic vasculitis, consistent with selectively suppressed neutrophil migration. In human blood microfluidic analysis, Nb-Fc treatment prevented collagen-induced fibrin deposition and neutrophil adhesion/activation. Thus, FXII is an important mediator of inflammatory responses in vasculitis and ECMO, and Nb-Fc provides a promising approach to alleviate thrombo-inflammatory disorders.

Date: 2024
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DOI: 10.1038/s41467-024-51745-4

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