Article
作者: Lunn, Kerry ; Ridley, Robert A ; Monk, Phillip D ; Brereton, Christopher J ; Roberts, James J W ; Sayer, Lucy N. ; Bell, Joseph A. ; Jogai, Sanjay ; Wickens, Leanne ; Jones, Mark G. ; Kaminski, Naftali ; Brereton, Christopher J. ; Vallejo, Andres F ; Davies, Donna E ; Vukmirovic, Milica ; Fabre, Aurelie ; Davies, Elizabeth R ; Davies, Donna E. ; Richeldi, Luca ; Ridley, Robert A. ; Alzetani, Aiman ; Marshall, Ben G ; Sayer, Lucy N ; Johnston, David A ; Davies, Elizabeth R. ; Vallejo, Andres F. ; Skipp, Paul ; Monk, Phillip D. ; Offer, Emily ; Roberts, James J.W. ; Jones, Mark G ; Conforti, Franco ; Wang, Yihua ; Johnston, David A. ; Marshall, Ben G. ; Bell, Joseph A ; Ceccato, Jessica
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.