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CC BY-NC-ND 4.0 · Thromb Haemost 2022; 122(02): 196-207
DOI: 10.1055/a-1663-8208
Coagulation and Fibrinolysis

Pharmacological Inhibition of Factor XIIa Attenuates Abdominal Aortic Aneurysm, Reduces Atherosclerosis, and Stabilizes Atherosclerotic Plaques

Amy K. Searle‡   *
1   Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia
2   Department of Medicine, Monash University, Melbourne, Australia
,
Yung-Chih Chen‡   *
1   Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia
2   Department of Medicine, Monash University, Melbourne, Australia
3   Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia
,
Maria Wallert‡   *
1   Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia
,
James D. McFadyen
1   Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia
2   Department of Medicine, Monash University, Melbourne, Australia
3   Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia
4   Clinical Haematology, Alfred Hospital, Melbourne, Australia
,
Ana C. Maluenda
1   Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia
,
Jonathan Noonan
1   Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia
3   Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia
,
Peter Kanellakis
5   Atherosclerosis and Cell Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia
,
Maria T. K. Zaldivia
1   Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia
,
Angela Huang
1   Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia
,
Hadi Lioe
6   CSL Limited, Bio21 Institute, Parkville, Melbourne, Australia
,
Mark Biondo
6   CSL Limited, Bio21 Institute, Parkville, Melbourne, Australia
,
Marc W. Nolte
7   CSL Behring Innovation GmbH, Marburg, Germany
,
Paolo Rossato
7   CSL Behring Innovation GmbH, Marburg, Germany
,
Alex Bobik
2   Department of Medicine, Monash University, Melbourne, Australia
5   Atherosclerosis and Cell Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia
8   Department of Immunology, Monash University, Melbourne, Australia
,
Con Panousis
6   CSL Limited, Bio21 Institute, Parkville, Melbourne, Australia
,
Xiaowei Wang‡   **
1   Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia
2   Department of Medicine, Monash University, Melbourne, Australia
3   Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia
,
Hamid Hosseini‡   **
1   Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia
,
Karlheinz Peter‡   **
1   Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia
2   Department of Medicine, Monash University, Melbourne, Australia
3   Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia
8   Department of Immunology, Monash University, Melbourne, Australia
9   Department of Cardiology, Alfred Hospital, Melbourne, Australia
› Author Affiliations
Funding This work was supported by the National Heart Foundation of Australia for A.K.S., Y.-C.C., J.D.M., and X.W.; by the German Research Foundation for M.W.; and by the National Health and Medical Research Council for J.D.M. and K.P. CSL Limited supported this research with an unrestricted research fund.
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Abstract

Background 3F7 is a monoclonal antibody targeting the enzymatic pocket of activated factor XII (FXIIa), thereby inhibiting its catalytic activity. Given the emerging role of FXIIa in promoting thromboinflammation, along with its apparent redundancy for hemostasis, the selective inhibition of FXIIa represents a novel and highly attractive approach targeting pathogenic processes that cause thromboinflammation-driven cardiovascular diseases.

Methods The effects of FXIIa inhibition were investigated using three distinct mouse models of cardiovascular disease—angiotensin II-induced abdominal aortic aneurysm (AAA), an ApoE−/− model of atherosclerosis, and a tandem stenosis model of atherosclerotic plaque instability. 3F7 or its isotype control, BM4, was administered to mice (10 mg/kg) on alternate days for 4 to 8 weeks, depending on the experimental model. Mice were examined for the development and size of AAAs, or the burden and instability of atherosclerosis and associated markers of inflammation.

Results Inhibition of FXIIa resulted in a reduced incidence of larger AAAs, with less acute aortic ruptures and an associated fibro-protective phenotype. FXIIa inhibition also decreased stable atherosclerotic plaque burden and achieved plaque stabilization associated with increased deposition of fibrous structures, a >2-fold thicker fibrous cap, increased cap-to-core ratio, and reduction in localized and systemic inflammatory markers.

Conclusion Inhibition of FXIIa attenuates disease severity across three mouse models of thromboinflammation-driven cardiovascular diseases. Specifically, the FXIIa-inhibiting monoclonal antibody 3F7 reduces AAA severity, inhibits the development of atherosclerosis, and stabilizes vulnerable plaques. Ultimately, clinical trials in patients with cardiovascular diseases such as AAA and atherosclerosis are warranted to demonstrate the therapeutic potential of FXIIa inhibition.

Keywords

3F7 monoclonal antibody - abdominal aortic aneurysm - atherosclerosis - coagulation factor XII - vulnerable plaques

Author Contributions

Y.-C.C., C.P., X.W., H.H., and K.P. designed the study. A.K.S., Y.-C.C., M.W., J.D.M., A.C.M., J.N., P.K., M.T.K.Z., A.H., H.L., M.B., M.W.N., P.R., X.W., and H.H. were involved in the acquisition and interpretation or analysis of data. A.K.S. drafted the manuscript. Y.-C.C., M.W., J.D.M., J.N., A.B., C.P., X.W., and K.P. provided critical review of the intellectual content of the manuscript. All authors approved the final version of the manuscript prior to submission.


* Equally contributing first authors.


** Equally contributing senior authors.


Supplementary Material



Publication History

Received: 30 April 2021

Accepted: 04 October 2021

Accepted Manuscript online:
07 October 2021

Article published online:
21 January 2022

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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