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

Author

Listed:
  • 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
    Zhejiang Normal University)

  • 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)

  • De-Pei Liu

    (Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Thomas Renné

    (University Medical Center Hamburg-Eppendorf (UKE)
    Johannes Gutenberg University Medical Center
    Royal College of Surgeons in Ireland)

  • Miao Wang

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Chinese Academy of Medical Sciences and Peking Union Medical College
    Central China Fuwai Hospital of Zhengzhou University)

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.

Suggested Citation

  • 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 & De-Pei Liu & Tho, 2024. "A single-domain antibody targeting factor XII inhibits both thrombosis and inflammation," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51745-4
    DOI: 10.1038/s41467-024-51745-4
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    as
    1. Jonas Wilbs & Xu-Dong Kong & Simon J. Middendorp & Raja Prince & Alida Cooke & Caitlin T. Demarest & Mai M. Abdelhafez & Kalliope Roberts & Nao Umei & Patrick Gonschorek & Christina Lamers & Kaycie De, 2020. "Cyclic peptide FXII inhibitor provides safe anticoagulation in a thrombosis model and in artificial lungs," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    2. Marco Heestermans & Clément Naudin & Reiner K. Mailer & Sandra Konrath & Kristin Klaetschke & Anne Jämsä & Maike Frye & Carsten Deppermann & Giordano Pula & Piotr Kuta & Manuel A. Friese & Mathias Gel, 2021. "Identification of the factor XII contact activation site enables sensitive coagulation diagnostics," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    3. Kerstin Göbel & Susann Pankratz & Chloi-Magdalini Asaridou & Alexander M. Herrmann & Stefan Bittner & Monika Merker & Tobias Ruck & Sarah Glumm & Friederike Langhauser & Peter Kraft & Thorsten F. Krug, 2016. "Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells," Nature Communications, Nature, vol. 7(1), pages 1-16, September.
    4. Liyuan Zhu & Chuansheng Xu & Xingyu Huo & Huifeng Hao & Qing Wan & Hong Chen & Xu Zhang & Richard M. Breyer & Yu Huang & Xuetao Cao & De-Pei Liu & Garret A. FitzGerald & Miao Wang, 2019. "The cyclooxygenase-1/mPGES-1/endothelial prostaglandin EP4 receptor pathway constrains myocardial ischemia-reperfusion injury," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    5. Joshua D. Ooi & Jhih-Hang Jiang & Peter J. Eggenhuizen & Ling L. Chua & Mirjan van Timmeren & Khai L. Loh & Kim M. O’Sullivan & Poh Y. Gan & Yong Zhong & Kirill Tsyganov & Lani R. Shochet & Jessica Ry, 2019. "A plasmid-encoded peptide from Staphylococcus aureus induces anti-myeloperoxidase nephritogenic autoimmunity," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
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