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

Spatial transcriptomic validation of a biomimetic model of fibrosis enables re-evaluation of a therapeutic antibody targeting LOXL2
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 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.
2666-3791
Bell, Joseph A.
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Davies, Elizabeth R.
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Brereton, Christopher J.
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Vukmirovic, Milica
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Roberts, James J.W.
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Lunn, Kerry
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Wickens, Leanne
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Conforti, Franco
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Ridley, Robert A.
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Ceccato, Jessica
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Sayer, Lucy N.
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Johnston, David A.
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Vallejo, Andres F.
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Alzetani, Aiman
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Marshall, Ben G.
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Fabre, Aurelie
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Richeldi, Luca
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Monk, Phillip D.
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Skipp, Paul
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Kaminski, Naftali
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Offer, Emily
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Jones, Mark
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Bell, Joseph A.
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Davies, Elizabeth R.
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Brereton, Christopher J.
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Vukmirovic, Milica
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Roberts, James J.W.
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Lunn, Kerry
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Wickens, Leanne
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Conforti, Franco
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Ridley, Robert A.
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Ceccato, Jessica
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Sayer, Lucy N.
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Johnston, David A.
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Vallejo, Andres F.
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Alzetani, Aiman
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Jogai, Sanjay
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Marshall, Ben G.
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Fabre, Aurelie
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Richeldi, Luca
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Monk, Phillip D.
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Skipp, Paul
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Kaminski, Naftali
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Offer, Emily
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Wang, Yihua
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Davies, Donna E.
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Jones, Mark
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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. (doi:10.1016/j.xcrm.2024.101695).

Record type: Article

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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Accepted/In Press date: 29 July 2024
e-pub ahead of print date: 21 August 2024

Identifiers

Local EPrints ID: 493054
URI: http://eprints.soton.ac.uk/id/eprint/493054
ISSN: 2666-3791
PURE UUID: 611fe90d-e8d0-42e8-9bcb-3a8fbfa52a28
ORCID for Elizabeth R. Davies: ORCID iD orcid.org/0000-0002-8629-8324
ORCID for David A. Johnston: ORCID iD orcid.org/0000-0001-6703-6014
ORCID for Andres F. Vallejo: ORCID iD orcid.org/0000-0002-4688-0598
ORCID for Paul Skipp: ORCID iD orcid.org/0000-0002-2995-2959
ORCID for Yihua Wang: ORCID iD orcid.org/0000-0001-5561-0648
ORCID for Donna E. Davies: ORCID iD orcid.org/0000-0002-5117-2991
ORCID for Mark Jones: ORCID iD orcid.org/0000-0001-6308-6014

Catalogue record

Date deposited: 22 Aug 2024 16:34
Last modified: 23 Aug 2024 01:52

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Contributors

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

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