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 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 antigen...
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Format: | Article |
Language: | English |
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eLife Sciences Publications Ltd
2021-08-01
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Series: | eLife |
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Online Access: | https://elifesciences.org/articles/67106 |
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Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies eLife organs-on-chips t-cell bispecifics cancer immunotherapy preclinical safety alveolar biology intestinal biology |
author_facet |
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 |
author_sort |
S Jordan Kerns |
title |
Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies |
title_short |
Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies |
title_full |
Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies |
title_fullStr |
Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies |
title_full_unstemmed |
Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies |
title_sort |
human immunocompetent organ-on-chip platforms allow safety profiling of tumor-targeted t-cell bispecific antibodies |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2021-08-01 |
description |
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. |
topic |
organs-on-chips t-cell bispecifics cancer immunotherapy preclinical safety alveolar biology intestinal biology |
url |
https://elifesciences.org/articles/67106 |
work_keys_str_mv |
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doaj-65e3b07242e4472a8bccea9ce9f5ca1b2021-08-18T11:53:28ZengeLife Sciences Publications LtdeLife2050-084X2021-08-011010.7554/eLife.67106Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodiesS Jordan Kerns0Chaitra Belgur1https://orcid.org/0000-0001-5670-6166Debora Petropolis2Marianne Kanellias3Riccardo Barrile4https://orcid.org/0000-0002-7301-3959Johannes Sam5Tina Weinzierl6Tanja Fauti7Anne Freimoser-Grundschober8Jan Eckmann9Carina Hage10Martina Geiger11Patrick Ray Ng12https://orcid.org/0000-0003-4566-9173William Tien-Street13Dimitris V Manatakis14Virginie Micallef15Regine Gerard16Michael Bscheider17Ekaterina Breous-Nystrom18Anneliese Schneider19Anna Maria Giusti20Cristina Bertinetti-Lapatki21Heather Shannon Grant22Adrian B Roth23Geraldine A Hamilton24Thomas Singer25Katia Karalis26Annie Moisan27Peter Bruenker28Christian Klein29Marina Bacac30Nikolce Gjorevski31https://orcid.org/0000-0001-8320-0443Lauriane Cabon32https://orcid.org/0000-0001-8472-2227Emulate Inc, Boston, United StatesEmulate Inc, Boston, United StatesEmulate Inc, Boston, United StatesEmulate Inc, Boston, United StatesEmulate Inc, Boston, United States; Department of Biomedical Engineering, University of Cincinnati, Cincinnati, United StatesRoche Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, SwitzerlandRoche Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, SwitzerlandRoche Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, SwitzerlandRoche Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, SwitzerlandRoche Pharma Research & Early Development, Roche Innovation Center Munich, Penzberg, GermanyRoche Pharma Research & Early Development, Roche Innovation Center Munich, Penzberg, GermanyRoche Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, SwitzerlandEmulate Inc, Boston, United StatesEmulate Inc, Boston, United StatesEmulate Inc, Boston, United StatesRoche Pharma Research & Early Development, Roche Innovation Center Basel, Basel, SwitzerlandRoche Pharma Research & Early Development, Roche Innovation Center Basel, Basel, SwitzerlandRoche Pharma Research & Early Development, Roche Innovation Center Basel, Basel, SwitzerlandRoche Pharma Research & Early Development, Roche Innovation Center Basel, Basel, SwitzerlandRoche Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, SwitzerlandRoche Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, SwitzerlandRoche Pharma Research & Early Development, Roche Innovation Center Basel, Basel, SwitzerlandEmulate Inc, Boston, United StatesRoche Pharma Research & Early Development, Roche Innovation Center Basel, Basel, SwitzerlandEmulate Inc, Boston, United StatesRoche Pharma Research & Early Development, Roche Innovation Center Basel, Basel, SwitzerlandEmulate Inc, Boston, United StatesRoche Pharma Research & Early Development, Roche Innovation Center Basel, Basel, SwitzerlandRoche Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, SwitzerlandRoche Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, SwitzerlandRoche Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, SwitzerlandRoche Pharma Research & Early Development, Roche Innovation Center Basel, Basel, SwitzerlandRoche Pharma Research & Early Development, Roche Innovation Center Basel, Basel, SwitzerlandTraditional 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.https://elifesciences.org/articles/67106organs-on-chipst-cell bispecificscancer immunotherapypreclinical safetyalveolar biologyintestinal biology |