Spatial transcriptomic validation of a biomimetic model of fibrosis enables re-evaluation of a therapeutic antibody targeting LOXL2
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.
Authors
- Leanne Wickens
- Milica Vukmirovic (ORCID: https://orcid.org/0000-0002-2025-3887)
- Aiman Alzetani (ORCID: https://orcid.org/0000-0002-3373-6714)
- Luca Richeldi (ORCID: https://orcid.org/0000-0001-8594-1448)
- James Roberts
- Andrés F. Vallejo (ORCID: https://orcid.org/0000-0002-4688-0598)
- Ben G. Marshall (ORCID: https://orcid.org/0000-0003-0946-0399)
- Donna E. Davies (ORCID: https://orcid.org/0000-0002-5117-2991)
- Joseph A. Bell (ORCID: https://orcid.org/0000-0002-3922-4795)
- Sanjay Jogai
- Aurélie Fabre (ORCID: https://orcid.org/0000-0001-8176-1386)
- Paul Skipp (ORCID: https://orcid.org/0000-0002-2995-2959)
- Franco Conforti (ORCID: https://orcid.org/0000-0001-5305-3155)
- Elizabeth R. Davies (ORCID: https://orcid.org/0000-0002-8629-8324)
- Christopher J. Brereton (ORCID: https://orcid.org/0000-0001-8302-702X)
- Emily Offer
- David A. Johnston (ORCID: https://orcid.org/0000-0001-6703-6014)
- Kerry Lunn
- Robert A. Ridley
- Naftali Kaminski (ORCID: https://orcid.org/0000-0001-5917-4601)
- Yihua Wang (ORCID: https://orcid.org/0000-0001-5561-0648)
- Mark G. Jones (ORCID: https://orcid.org/0000-0001-6308-6014)
- Jessica Ceccato
- Lucy N Sayer
- Phillip Monk
Institutions
- University College Dublin (IE)
- University of Padua (IT)
- Southampton General Hospital (GB)
- Yale University (US)
- Medicines Discovery Catapult (GB)
- NIHR Southampton Respiratory Biomedical Research Unit (GB)
- St. Vincent's University Hospital (IE)
- NIHR Southampton Biomedical Research Centre (GB)
- Synairgen (United Kingdom) (GB)
- University of Southampton (GB)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-08-23
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101695
- Citations
- 6
- Primary Topic
- Microbial metabolism and enzyme function
- Type
- article
- Field-Weighted Citation Impact
- 1.40
Funders
- Gilead Sciences
- Wellcome Trust
- National Institute for Health and Care Research
- AAIR Charity
- National Institute for Health Research Southampton Biomedical Research Centre
- Medical Research Council
- Biotechnology and Biological Sciences Research Council