Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies.
S Jordan KernsChaitra BelgurDebora PetropolisMarianne KanelliasRiccardo BarrileJohannes SamTina WeinzierlTanja FautiAnne Freimoser-GrundschoberJan EckmannCarina HageMartina GeigerPatrick Ray NgWilliam Tien-StreetDimitris V ManatakisVirginie MicallefRegine GerardMichael BscheiderEkaterina Breous-NystromAnneliese SchneiderAnna Maria GiustiCristina Bertinetti-LapatkiHeather Shannon GrantAdrian B RothGeraldine A HamiltonThomas SingerKatia KaralisAnnie MoisanPeter BruenkerChristian KleinMarina BacacNikolce GjorevskiLauriane CabonPublished in: eLife (2021)
Traditional drug safety assessment often fails to predict complications in humans, especially when the drug targets the immune system. Here, we show the unprecedented capability of two human Organs-on-Chips to evaluate the safety profile of T-cell bispecific antibodies (TCBs) targeting tumor antigens. Although promising for cancer immunotherapy, TCBs are associated with an on-target, off-tumor risk due to low levels of expression of tumor antigens in healthy tissues. We leveraged in vivo target expression and toxicity data of TCBs targeting folate receptor 1 (FOLR1) or carcinoembryonic antigen (CEA) to design and validate human immunocompetent Organs-on-Chips safety platforms. We discovered that the Lung-Chip and Intestine-Chip could reproduce and predict target-dependent TCB safety liabilities, based on sensitivity to key determinants thereof, such as target expression and antibody affinity. These novel tools broaden the research options available for mechanistic understandings of engineered therapeutic antibodies and assessing safety in tissues susceptible to adverse events.