An activity‐based bioprobe differentiates a novel small molecule inhibitor from a LOXL2 antibody and provides renewed promise for anti‐fibrotic therapeutic strategies

Dear Editor, In this study, measurement of target inhibition of lysyl oxidase-like 2 (LOXL2) in a high throughput manner from tissue lysates and blood was achieved by the tailored design of an activity-based probe (ABP), PXS-5878. Lysyl oxidases are a family of five enzymes critically responsible for the formation of cross-linked collagen and elastin, the hallmarks of fibrosis and stroma.1,2 One member in particular, LOXL2, has excellent pre-clinical target validation, is upregulated in various fibrotic diseases and cancer,3 and acts as a biomarker for disease severity and progression in humans.4,5 Despite overwhelming target rationale, the failure of the LOXL2 antibody simtuzumab to achieve positive clinical endpoints6,7 has undoubtedly hampered progress in the field and cast doubt over the validity of LOXL2 inhibition as a viable therapeutic approach. SEE PDF] In clinical studies with simtuzumab, the humanised version of AB0023, target engagement in human blood was not measured, triggering uncertainty about the lack of efficacy in humans.