Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies

Traditional drug safety assessment often fails to predict complications in humans, especially when the targets immune system. Here, we show unprecedented capability of two human Organs-on-Chips evaluate profile T-cell bispecific antibodies (TCBs) targeting tumor antigens. Although promising for cancer immunotherapy, TCBs are associated with an on-target, off-tumor risk due low levels expression antigens healthy tissues. We leveraged vivo target and toxicity data folate receptor 1 (FOLR1) or carcinoembryonic antigen (CEA) design validate immunocompetent platforms. discovered that Lung-Chip Intestine-Chip could reproduce target-dependent TCB liabilities, based on sensitivity key determinants thereof, such as antibody affinity. These novel tools broaden research options available mechanistic understandings engineered therapeutic assessing tissues susceptible adverse events.