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

Cell Rep Med. 2024 Sep 17;5(9):101695. doi: 10.1016/j.xcrm.2024.101695. Epub 2024 Aug 21.

Abstract

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.

Keywords: LOXL2; disease-relevant biomimetic models; fibrosis; spatial transcriptomics; target engagement.

MeSH terms

  • Amino Acid Oxidoreductases* / genetics
  • Amino Acid Oxidoreductases* / metabolism
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Biomimetics / methods
  • Collagen / metabolism
  • Fibrosis*
  • Humans
  • Models, Biological
  • Transcriptome* / genetics

Substances

  • Amino Acid Oxidoreductases
  • LOXL2 protein, human
  • Collagen
  • Antibodies, Monoclonal, Humanized