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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Main 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
Format: Article
Language:English
Published: eLife Sciences Publications Ltd 2021-08-01
Series:eLife
Subjects:
Online Access:https://elifesciences.org/articles/67106
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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
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spelling 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