TY - JOUR TI - Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies AU - Kerns, S Jordan AU - Belgur, Chaitra AU - Petropolis, Debora AU - Kanellias, Marianne AU - Barrile, Riccardo AU - Sam, Johannes AU - Weinzierl, Tina AU - Fauti, Tanja AU - Freimoser-Grundschober, Anne AU - Eckmann, Jan AU - Hage, Carina AU - Geiger, Martina AU - Ng, Patrick Ray AU - Tien-Street, William AU - Manatakis, Dimitris V AU - Micallef, Virginie AU - Gerard, Regine AU - Bscheider, Michael AU - Breous-Nystrom, Ekaterina AU - Schneider, Anneliese AU - Giusti, Anna Maria AU - Bertinetti-Lapatki, Cristina AU - Grant, Heather Shannon AU - Roth, Adrian B AU - Hamilton, Geraldine A AU - Singer, Thomas AU - Karalis, Katia AU - Moisan, Annie AU - Bruenker, Peter AU - Klein, Christian AU - Bacac, Marina AU - Gjorevski, Nikolce AU - Cabon, Lauriane A2 - Ho, Ping-Chih A2 - Diamond, Betty A2 - Ho, Ping-Chih VL - 10 PY - 2021 DA - 2021/08/11 SP - e67106 C1 - eLife 2021;10:e67106 DO - 10.7554/eLife.67106 UR - https://doi.org/10.7554/eLife.67106 AB - 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. KW - organs-on-chips KW - t-cell bispecifics KW - cancer immunotherapy KW - preclinical safety KW - alveolar biology KW - intestinal biology JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -