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

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A single-domain antibody targeting factor XII inhibits both thrombosis and inflammation. / Xu, Pengfei; Zhang, Yingjie; Guo, Junyan; Li, Huihui; Konrath, Sandra; Zhou, Peng; Cai, Liming ; Rao, Haojie; Chen, Hong; Lin, Jian; Cui, Zhao; Ji, Bingyang; Wang, Jianwei; Li, Nailin; Liu, De-Pei; Renne, Thomas; Wang, Miao.

In: NAT COMMUN, Vol. 15, No. 1, 12.09.2024, p. 7898 - 7912.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Xu, P, Zhang, Y, Guo, J, Li, H, Konrath, S, Zhou, P, Cai, L, Rao, H, Chen, H, Lin, J, Cui, Z, Ji, B, Wang, J, Li, N, Liu, D-P, Renne, T & Wang, M 2024, 'A single-domain antibody targeting factor XII inhibits both thrombosis and inflammation', NAT COMMUN, vol. 15, no. 1, pp. 7898 - 7912. https://doi.org/10.1038/s41467-024-51745-4

APA

Xu, P., Zhang, Y., Guo, J., Li, H., Konrath, S., Zhou, P., Cai, L., Rao, H., Chen, H., Lin, J., Cui, Z., Ji, B., Wang, J., Li, N., Liu, D-P., Renne, T., & Wang, M. (2024). A single-domain antibody targeting factor XII inhibits both thrombosis and inflammation. NAT COMMUN, 15(1), 7898 - 7912. https://doi.org/10.1038/s41467-024-51745-4

Vancouver

Xu P, Zhang Y, Guo J, Li H, Konrath S, Zhou P et al. A single-domain antibody targeting factor XII inhibits both thrombosis and inflammation. NAT COMMUN. 2024 Sep 12;15(1):7898 - 7912. https://doi.org/10.1038/s41467-024-51745-4

Bibtex

@article{558822b8927b487f9bd22a06984d758d,
title = "A single-domain antibody targeting factor XII inhibits both thrombosis and inflammation",
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.",
author = "Pengfei Xu and Yingjie Zhang and Junyan Guo and Huihui Li and Sandra Konrath and Peng Zhou and Liming Cai and Haojie Rao and Hong Chen and Jian Lin and Zhao Cui and Bingyang Ji and Jianwei Wang and Nailin Li and De-Pei Liu and Thomas Renne and Miao Wang",
year = "2024",
month = sep,
day = "12",
doi = "10.1038/s41467-024-51745-4",
language = "English",
volume = "15",
pages = "7898 -- 7912",
journal = "NAT COMMUN",
issn = "2041-1723",
publisher = "NATURE PUBLISHING GROUP",
number = "1",

}

RIS

TY - JOUR

T1 - A single-domain antibody targeting factor XII inhibits both thrombosis and inflammation

AU - Xu, Pengfei

AU - Zhang, Yingjie

AU - Guo, Junyan

AU - Li, Huihui

AU - Konrath, Sandra

AU - Zhou, Peng

AU - Cai, Liming

AU - Rao, Haojie

AU - Chen, Hong

AU - Lin, Jian

AU - Cui, Zhao

AU - Ji, Bingyang

AU - Wang, Jianwei

AU - Li, Nailin

AU - Liu, De-Pei

AU - Renne, Thomas

AU - Wang, Miao

PY - 2024/9/12

Y1 - 2024/9/12

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-024-51745-4

DO - 10.1038/s41467-024-51745-4

M3 - SCORING: Journal article

C2 - 39266545

VL - 15

SP - 7898

EP - 7912

JO - NAT COMMUN

JF - NAT COMMUN

SN - 2041-1723

IS - 1

ER -