Bell, Joseph A., Davies, Elizabeth R., Brereton, Christopher J., Vukmirovic, Milica, Roberts, James J.W., Lunn, Kerry, Wickens, Leanne, Conforti, Franco, Ridley, Robert A., Ceccato, Jessica, Sayer, Lucy N., Johnston, David A., Vallejo, Andres F., Alzetani, Aiman, Jogai, Sanjay, Marshall, Ben G., Fabre, Aurelie, Richeldi, Luca, Monk, Phillip D., Skipp, Paul, Kaminski, Naftali, Offer, Emily, Wang, Yihua, Davies, Donna E. and Jones, Mark (2024) Spatial transcriptomic validation of a biomimetic model of fibrosis enables re-evaluation of a therapeutic antibody targeting LOXL2. Cell Reports Medicine, 5 (9), [101695]. (doi:10.1016/j.xcrm.2024.101695).
Abstract
Matrix stiffening by lysyl oxidase-like 2 (LOXL2) mediated collagen cross-linking is proposed as a core feed-forward mechanism that promotes fibrogenesis. Failure in clinical trials of simtuzumab (the humanized version of AB0023, a monoclonal antibody against human LOXL2) suggested 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 interpretation of lack of efficacy of simtuzumab in clinical trials of fibrotic diseases.
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