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

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.

• Authors: Amy K Searle, Yung-Chih Chen, Maria Wallert, James D McFadyen, Ana C Maluenda, Jonathan Noonan, Peter Kanellakis, Maria T K Zaldivia, Angela Huang, Hadi Lioe, Mark Biondo, Marc W Nolte, Paolo Rossato, Alex Bobik, Con Panousis, Xiaowei Wang, Hamid Hosseini, Karlheinz Peter
• Journal: Thrombosis and haemostasis (Thromb Haemost) Vol. 122 Issue 2 Pg. 196-207 (02 2022) ISSN: 2567-689X [Electronic] Germany
• PMID: 34619795 (Publication Type: Journal Article)
• Copyright: 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/).

Chemical References

• Antibodies, Monoclonal
• Apolipoproteins E
• Factor XIIa

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage)
• Aortic Aneurysm, Abdominal (epidemiology, prevention & control)
• Apolipoproteins E
• Atherosclerosis (prevention & control)
• Disease Models, Animal
• Factor XIIa (antagonists & inhibitors)
• Inflammation
• Male
• Mice
• Plaque, Atherosclerotic (metabolism)