A patient-derived lung-on-chip model to evaluate on-target/off-tumour toxicity of the therapeutic FOLR1-targeting T-Cell Bispecific antibody

The overexpression of Folate-receptor 1 (FOLR1) in various types of cancer (ovarian, lung, renal), makes it an attractive candidate for targeted-tumour immunotherapy. T-cell bispecific antibodies are engineered to recognize both FOLR1 and the T-cell receptor CD3 (FOLR1-TCB), enhancing tumour recognition, assault and killing by T-cells. Despite their therapeutic potential, such antibodies present the risk of on-target/off-tumour toxicity, as FOLR1 is also expressed in healthy epithelial cells in the lung or the kidney.In this work, FOLR1-TCB pulmonary toxicity was evaluated using an advanced lung-on-chip in-vitro model. With that purpose, human epithelial and/or endothelial barrier models were treated with FOLR1-TCB in the presence of peripheral blood mononuclear cells (PBMC). According to our results, FOLR1-TCB induced a pronounced on-target/off-tumour damage in our alveolar model as indicated by increased cytotoxicity, barrier leakage (TER) and pro-inflammatory cytokine release (e.g., IL-6, Granzyme B). Additionally, FOLR1-TCB treatment induced T-cell specific activation, as observed by flow cytometry analysis, as well as targeted attachment to the epithelium, as detected by live imaging tracking.Taken together, our results suggest that our patient-derived alveolar lung-on-chip model can successfully predict off-tumour TCB adverse effects. This highlights the importance of considering the immune component, allowing cell-cell interactions, and providing an in-vivo-like microe...
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Mechanisms of lung injury and repair Source Type: research