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.

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.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Factor XII* / antagonists & inhibitors
  • Factor XII* / metabolism
  • Factor XIIa / antagonists & inhibitors
  • Factor XIIa / metabolism
  • Fibrin / metabolism
  • Fibrin Fibrinogen Degradation Products / metabolism
  • Humans
  • Inflammation* / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout*
  • Neutrophils* / drug effects
  • Neutrophils* / immunology
  • Neutrophils* / metabolism
  • Platelet Aggregation / drug effects
  • Single-Domain Antibodies* / immunology
  • Single-Domain Antibodies* / pharmacology
  • Thrombosis* / immunology
  • Thrombosis* / metabolism

Substances

  • Single-Domain Antibodies
  • Factor XII
  • Factor XIIa
  • Fibrin
  • Fibrin Fibrinogen Degradation Products