Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies
S. Jordan Kerns, Chaitra Belgur, Debora B. Petropolis, Marianne Kanellias, Riccardo Barrile, Johannes Sam, Tina Weinzierl, Tanja Fauti, Anne Freimoser–Grundschober, Jan Eckmann, Carina Hage, Martina Geiger, Patrick R. Ng, William Tien-Street, Dimitris V. Manatakis, Virginie Micallef, Régine Gérard, Michael Bscheider, Ekaterina Breous-Nystrom, Anneliese Schneider, Anna Maria Giusti, Cristina Bertinetti‐Lapatki, Heather Shannon Grant, Adrian Roth, Geraldine A. Hamilton, Thomas P. Singer, Katia Karalis, Annie Moisan, Peter Bruenker, Christian Klein, Marina Bacac, Nikolce Gjorevski, Lauriane Cabon
Abstract
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.