2. Academic Validation
  3. A single-domain antibody targeting factor XII inhibits both thrombosis and inflammation

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

  • Nat Commun. 2024 Sep 12;15(1):7898. doi: 10.1038/s41467-024-51745-4.
Pengfei Xu # 1,  Yingjie Zhang # 1,  Junyan Guo 1 2,  Huihui Li 1,  Sandra Konrath 3,  Peng Zhou 4,  Liming Cai 5,  Haojie Rao 1,  Hong Chen 1,  Jian Lin 4,  Zhao Cui 6,  Bingyang Ji 5,  Jianwei Wang 7,  Nailin Li 8,  De-Pei Liu 9,  Thomas Renné 3 10 11,  Miao Wang 12 13 14
Affiliations

Affiliations

  • 1 State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 2 College of Life Science, Zhejiang Normal University, Jinhua, Zhejiang, China.
  • 3 Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
  • 4 Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
  • 5 Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 6 Renal Division, Peking University First Hospital, Beijing, China.
  • 7 MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 8 Department of Medicine-Solna, Cardiovascular Medicine Unit, Karolinska Institute, Stockholm, Sweden.
  • 9 Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 10 Center for Thrombosis and Hemostasis (CTH), Johannes Gutenberg University Medical Center, Mainz, Germany.
  • 11 Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.
  • 12 State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. miao.wang@pumc.edu.cn.
  • 13 Clinical Pharmacology Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. miao.wang@pumc.edu.cn.
  • 14 National Health Commission Cardiovascular Disease Regenerative Medicine Research Key Laboratory, Central China Subcenter of National Center for Cardiovascular Diseases, Henan Cardiovascular Disease Center, Fuwai Central-China Cardiovascular Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, China. miao.wang@pumc.edu.cn.
  • # Contributed equally.
PMID: 39266545 DOI: 10.1038/s41467-024-51745-4
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.

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