Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK; NIHR Southampton Biomedical Research Centre, University Hospital Southampton, SO16 6YD Southampton, UK.
Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK; NIHR Southampton Biomedical Research Centre, University Hospital Southampton, SO16 6YD Southampton, UK; Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, SO17 1BJ Southampton, UK.
Cell Rep Med. 2024 Sep 17;5(9):101695. doi: 10.1016/j.xcrm.2024.101695. Epub 2024 Aug 21.
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.
赖氨酰氧化酶样蛋白 2（LOXL2）介导的胶原蛋白交联导致基质变硬，被认为是促进纤维化的核心前馈机制。在 simtuzumab（AB0023 的人源化版本，一种针对人 LOXL2 的单克隆抗体）的临床试验中失败表明，针对 LOXL2 可能与疾病无关；然而，并未直接评估靶标结合。我们将活跃的人类肺纤维化部位的空间转录组与不同的人类细胞培养模型进行比较，以确定与疾病相关的模型。然后，在选定的模型中评估 AB0023，发现它不能抑制胶原蛋白交联或降低组织硬度，也不能抑制 LOXL2 的催化活性。相比之下，它确实强烈抑制血管生成，与替代的非酶促作用机制一致。因此，AB0023 具有抗血管生成作用，但不能抑制 LOXL2 的催化活性、胶原蛋白交联或组织僵硬。这些发现对解释 simtuzumab 在纤维化疾病临床试验中缺乏疗效具有重要意义。
