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

Authors :
S Jordan Kerns
Chaitra Belgur
Debora Petropolis
Marianne Kanellias
Riccardo Barrile
Johannes Sam
Tina Weinzierl
Tanja Fauti
Anne Freimoser-Grundschober
Jan Eckmann
Carina Hage
Martina Geiger
Patrick Ray Ng
William Tien-Street
Dimitris V Manatakis
Virginie Micallef
Regine Gerard
Michael Bscheider
Ekaterina Breous-Nystrom
Anneliese Schneider
Anna Maria Giusti
Cristina Bertinetti-Lapatki
Heather Shannon Grant
Adrian B Roth
Geraldine A Hamilton
Thomas Singer
Katia Karalis
Annie Moisan
Peter Bruenker
Christian Klein
Marina Bacac
Nikolce Gjorevski
Lauriane Cabon
Source :
eLife, Vol 10 (2021)
Publication Year :
2021
Publisher :
eLife Sciences Publications Ltd, 2021.

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.

Details

Language :
English
ISSN :
2050084X
Volume :
10
Database :
Directory of Open Access Journals
Journal :
eLife
Publication Type :
Academic Journal
Accession number :
edsdoj.65e3b07242e4472a8bccea9ce9f5ca1b
Document Type :
article
Full Text :
https://doi.org/10.7554/eLife.67106