Safety evaluation of cancer immunotherapy in a lung-on-chip model: the therapeutic FOLR1 targeting T Cell Bispecific antibody

Abstract

Folate-receptor 1 (FOLR1) is overexpressed in many types of cancer (ovarian, lung, renal), making it a suitable target for targeted-tumour therapies. FOLR1/CD3 T-cell bispecific antibodies (FOLR1-TCB) are engineered to recognize both FOLR1 and the T-cell receptor, enhancing tumour targeting by T-cells, recognition and killing. Because FOLR1 is also expressed in normal epithelial cells in the lung or the kidney, albeit at lower levels, such therapeutic antibodies present the risk of an on-target/off-tumour toxicity.

In this work, we have used an advanced lung-on-chip in-vitro model (LOC) to evaluate FOLR1-TCB expected pulmonary toxicity. With that purpose, human epithelial and/or endothelial barrier models were treated with FOLR1-TCB in presence of peripheral blood mononuclear cells (PBMC). According to our results, we successfully reproduced FOLR1-TCB on-target/off-tumour alveolar damage as indicated by pro-inflammatory cytokine release (e.g. IL-6, Granzyme B), increased cytotoxicity and barrier leakage (TEER). Additionally, FOLR1-TCB treatment induced T cell specific activation and proliferation, as observed by flow cytometry analysis.

Altogether, our data suggests that our alveolar cell model on the lung-on-chip system can successfully predict off-tumour toxic TCB effects. This highlights the relevance of complex in vitro models supporting physiological cell-cell interactions and an in-vivo-like microenvironment for safety evaluation of therapeutic antibodies before their entry into the clinics.