Spatial transcriptomic validation of a biomimetic model of fibrosis enables re-evaluation of a therapeutic antibody targeting LOXL2

作者：Joseph A. Bell, Elizabeth R. Davies, Christopher J. Brereton, Milica Vukmirovic, James Roberts, Kerry Lunn, Leanne Wickens, Franco Conforti, Robert A. Ridley, Jessica Ceccato, Lucy N Sayer, David A. Johnston, Andrés F. Vallejo, Aiman Alzetani, Sanjay Jogai, Ben G. Marshall, Aurélie Fabre, Luca Richeldi, Phillip Monk, Paul Skipp, Naftali Kaminski, Emily Offer, Yihua Wang, Donna E. Davies, Mark G. Jones · 发表于：Cell Reports Medicine · 年份：2024 · DOI：10.1016/j.xcrm.2024.101695 · 被引用次数：9 · 研究领域：Microbial metabolism and enzyme function、Galectins and Cancer Biology、Cell Adhesion Molecules Research

Matrix stiffening by lysyl oxidase-like 2 (LOXL2)-mediated collagen cross-linking is proposed as a core feedforward mechanism that promotes fibrogenesis. Failure in clinical trials of simtuzumab (the humanized version of AB0023, a monoclonal antibody against human LOXL2) suggested that targeting LOXL2 may not have disease relevance; however, target engagement was not directly evaluated. We compare the spatial transcriptome of active human lung fibrogenesis sites with different human cell culture models to identify a disease-relevant model. Within the selected model, we then evaluate AB0023, identifying that it does not inhibit collagen cross-linking or reduce tissue stiffness, nor does it inhibit LOXL2 catalytic activity. In contrast, it does potently inhibit angiogenesis consistent with an alternative, non-enzymatic mechanism of action. Thus, AB0023 is anti-angiogenic but does not inhibit LOXL2 catalytic activity, collagen cross-linking, or tissue stiffening. These findings have implications for the interpretation of the lack of efficacy of simtuzumab in clinical trials of fibrotic diseases. • Spatial multi-omics identifies a disease-relevant model of lung fibrosis • A 3D model recapitulates gene and protein expression patterns of fibroblast foci • Target engagement and functional fibrosis assays within the validated 3D model • Anti-LOXL2 antibody AB0023/simtuzumab does not inhibit LOXL2 catalytic activity Bell et al. compare the spatial transcriptome of human lung fibrogene...