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.

Data availability

RNA sequencing data have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus (GEO) under accession number GSE175821 and it is currently accessible to reviewers with the token (shihmgyujnanvuh) before its public release on Sep 1st.

The following data sets were generated

Article and author information

Author details

  1. S Jordan Kerns

    Research and Development, Emulate Inc, Boston, United States
    Competing interests
    S Jordan Kerns, Is a current employee of and hold equity interests or options to obtain equity interests in Emulate Inc.Is an inventor on a patent application (P16451EP00/16/912,391) submitted by Hoffmann-LaRoche and Emulate that covers 'Method for Assessing a Compound Interacting with a Target on Epithelial Cells'.
  2. Chaitra Belgur

    Research and Development, Emulate Inc, Boston, United States
    Competing interests
    Chaitra Belgur, Is a former employee of and hold equity interests or options to obtain equity interests in Emulate Inc.Is an inventor on a patent application (P16451EP00/16/912,391) submitted by Hoffmann-LaRoche and Emulate that covers 'Method for Assessing a Compound Interacting with a Target on Epithelial Cells'.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5670-6166
  3. Debora Petropolis

    Cell Biology and Infection, Emulate Inc, Boston, United States
    Competing interests
    Debora Petropolis, Is a former employee of and hold equity interests or options to obtain equity interests in Emulate Inc.Is an inventor on a patent application (P16451EP00/16/912,391) submitted by Hoffmann-LaRoche and Emulate that covers Method for Assessing a Compound Interacting with a Target on Epithelial Cells,.
  4. Marianne Kanellias

    Research and Development, Emulate Inc, Boston, United States
    Competing interests
    Marianne Kanellias, Is a current or former employee of and hold equity interests or options to obtain equity interests in Emulate Inc..
  5. Riccardo Barrile

    Research and Development, Emulate Inc., Boston, United States
    Competing interests
    Riccardo Barrile, Is a former employee of and hold equity interests or options to obtain equity interests in Emulate Inc.Is an inventor on a patent application (P16451EP00/16/912,391) submitted by Hoffmann-LaRoche and Emulate that covers ,Method for Assessing a Compound Interacting with a Target on Epithelial Cells'.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7301-3959
  6. Johannes Sam

    Pharmacology, Roche pRED, Schlieren, Switzerland
    Competing interests
    Johannes Sam, Employment, patents and ownership of stock with Roche..
  7. Tina Weinzierl

    Oncology, Roche pRED, Schlieren, Switzerland
    Competing interests
    Tina Weinzierl, Employment, patents and ownership of stock with Roche..
  8. Tanja Fauti

    Oncology, Roche pRED, Schlieren, Switzerland
    Competing interests
    Tanja Fauti, Employment, patents and ownership of stock with Roche..
  9. Anne Freimoser-Grundschober

    Oncology, Roche pRED, Schlieren, Switzerland
    Competing interests
    Anne Freimoser-Grundschober, Employment, patents and ownership of stock with Roche..
  10. Jan Eckmann

    Pharmacology, Roche pRED, Penzberg, Germany
    Competing interests
    Jan Eckmann, Employment, patents and ownership of stock with Roche..
  11. Carina Hage

    Pharmacology, Roche pRED, Penzberg, Germany
    Competing interests
    Carina Hage, Employment and ownership of stock with Roche..
  12. Martina Geiger

    Oncology, Roche pRED, Schlieren, Switzerland
    Competing interests
    Martina Geiger, Employment, patents and ownership of stock with Roche..
  13. Patrick Ray Ng

    Research and Development, Emulate Inc, Boston, United States
    Competing interests
    Patrick Ray Ng, is a former employee of and hold equity interests or options to obtain equity interests in Emulate Inc..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4566-9173
  14. William Tien-Street

    Research and Development, Emulate Inc, Boston, United States
    Competing interests
    William Tien-Street, is a current employee of and hold equity interests or options to obtain equity interests in Emulate Inc..
  15. Dimitris V Manatakis

    Research and Development, Emulate Inc, Boston, United States
    Competing interests
    Dimitris V Manatakis, Is a current employee of and hold equity interests or options to obtain equity interests in Emulate Inc..
  16. Virginie Micallef

    Pharmaceutical Sciences, Roche pRED, Basel, Switzerland
    Competing interests
    Virginie Micallef, Employment and ownership of stock with Roche..
  17. Regine Gerard

    Pharmaceutical Sciences, Roche pRED, Basel, Switzerland
    Competing interests
    Regine Gerard, Employment and ownership of stock with Roche..
  18. Michael Bscheider

    Pharmaceutical Sciences, Roche pRED, Basel, Switzerland
    Competing interests
    Michael Bscheider, Employment and ownership of stock with Roche..
  19. Ekaterina Breous-Nystrom

    Pharmaceutical Sciences, Roche pRED, Basel, Switzerland
    Competing interests
    Ekaterina Breous-Nystrom, Employment and ownership of stock with Roche..
  20. Anneliese Schneider

    Pharmaceutical Sciences, Roche pRED, Schlieren, Switzerland
    Competing interests
    Anneliese Schneider, Employment, patents and ownership of stock with Roche..
  21. Anna Maria Giusti

    Pharmaceutical Sciences, Roche pRED, Schlieren, Switzerland
    Competing interests
    Anna Maria Giusti, Employment, patents and ownership of stock with Roche..
  22. Cristina Bertinetti-Lapatki

    Pharmaceutical Sciences, Roche pRED, Basel, Switzerland
    Competing interests
    Cristina Bertinetti-Lapatki, Is an inventor on a patent application (P16451EP00/16/912,391) submitted by Hoffmann-LaRoche and Emulate that covers 'Method for Assessing a Compound Interacting with a Target on Epithelial Cells'. Employment, patents and ownership of stock with Roche..
  23. Heather Shannon Grant

    Research and Development, Emulate Inc., Boston, United States
    Competing interests
    Heather Shannon Grant, Is a former employee of and hold equity interests or options to obtain equity interests in Emulate Inc.Is an inventor on a patent application (P16451EP00/16/912,391) submitted by Hoffmann-LaRoche and Emulate that covers 'Method for Assessing a Compound Interacting with a Target on Epithelial Cells'.
  24. Adrian B Roth

    Pharma Development, Roche pRED, Basel, Switzerland
    Competing interests
    Adrian B Roth, Is an inventor on a patent application (P16451EP00/16/912,391) submitted by Hoffmann-LaRoche and Emulate that covers 'Method for Assessing a Compound Interacting with a Target on Epithelial Cells'. Employment, patents and ownership of stock with Roche..
  25. Geraldine A Hamilton

    Research and Development, Emulate Inc, Boston, United States
    Competing interests
    Geraldine A Hamilton, Is a current or former employee of and hold equity interests or options to obtain equity interests in Emulate Inc.Is an inventor on a patent application (P16451EP00/16/912,391) submitted by Hoffmann-LaRoche and Emulate that covers 'Method for Assessing a Compound Interacting with a Target on Epithelial Cells'.
  26. Thomas Singer

    Pharmaceutical Sciences, Roche pRED, Basel, Switzerland
    Competing interests
    Thomas Singer, Employment, patents and ownership of stock with Roche..
  27. Katia Karalis

    Research and Development, Emulate Inc., Boston, United States
    Competing interests
    Katia Karalis, Is a former employee of and hold equity interests or options to obtain equity interests in Emulate Inc.Is an inventor on a patent application (P16451EP00/16/912,391) submitted by Hoffmann-LaRoche and Emulate that covers 'Method for Assessing a Compound Interacting with a Target on Epithelial Cells'.
  28. Annie Moisan

    Pharmaceutical Sciences, Roche pRED, Basel, Switzerland
    Competing interests
    Annie Moisan, is an inventor on a patent application (P16451EP00/16/912,391) submitted by Hoffmann-LaRoche and Emulate that covers Method for Assessing a Compound Interacting with a Target on Epithelial Cells'..
  29. Peter Bruenker

    Oncology, Roche pRED, Schlieren, Switzerland
    Competing interests
    No competing interests declared.
  30. Christian Klein

    Oncology, Roche pRED, Schlieren, Switzerland
    Competing interests
    Christian Klein, Employment, patents and ownership of stock with Roche..
  31. Marina Bacac

    Oncology, Roche pRED, Schlieren, Switzerland
    Competing interests
    Marina Bacac, Employment, patents and ownership of stock with Roche..
  32. Nikolce Gjorevski

    Pharmaceutical Sciences, Roche pRED, Basel, Switzerland
    For correspondence
    nikolche.gjorevski@roche.com
    Competing interests
    Nikolce Gjorevski, is an inventor on a patent application (P16451EP00/16/912,391) submitted by Hoffmann-LaRoche and Emulate that covers Method for Assessing a Compound Interacting with a Target on Epithelial Cells'. Employment, patents and ownership of stock with Roche..
  33. Lauriane Cabon

    Pharmaceutical Sciences, Roche pRED, Basel, Switzerland
    For correspondence
    lauriane.cabon@roche.com
    Competing interests
    Lauriane Cabon, is an inventor on a patent application (P16451EP00/16/912,391) submitted by Hoffmann-LaRoche and Emulate that covers Method for Assessing a Compound Interacting with a Target on Epithelial Cells'. Employment, patents and ownership of stock with Roche..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8472-2227

Funding

The authors declare that there was no funding for this work.

Ethics

Animal experimentation: The animal facility has been accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). All animal studies were performed in accordance with the Federation for Laboratory Animal Science Associations (FELASA). The animal studies were approved by and done under license from the Government of Upper Bavaria (Regierung von Oberbayern; Approval number: Az 55.2.1.54-2532.0-10-16). We have complied with all relevant ethical guidelines and regulations.

Reviewing Editor

  1. Ping-Chih Ho, Ludwig Institute for Cancer Research, Switzerland

Publication history

  1. Received: January 31, 2021
  2. Preprint posted: February 22, 2021 (view preprint)
  3. Accepted: August 10, 2021
  4. Accepted Manuscript published: August 11, 2021 (version 1)
  5. Version of Record published: August 18, 2021 (version 2)

Copyright

© 2021, Kerns et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. S Jordan Kerns
  2. Chaitra Belgur
  3. Debora Petropolis
  4. Marianne Kanellias
  5. Riccardo Barrile
  6. Johannes Sam
  7. Tina Weinzierl
  8. Tanja Fauti
  9. Anne Freimoser-Grundschober
  10. Jan Eckmann
  11. Carina Hage
  12. Martina Geiger
  13. Patrick Ray Ng
  14. William Tien-Street
  15. Dimitris V Manatakis
  16. Virginie Micallef
  17. Regine Gerard
  18. Michael Bscheider
  19. Ekaterina Breous-Nystrom
  20. Anneliese Schneider
  21. Anna Maria Giusti
  22. Cristina Bertinetti-Lapatki
  23. Heather Shannon Grant
  24. Adrian B Roth
  25. Geraldine A Hamilton
  26. Thomas Singer
  27. Katia Karalis
  28. Annie Moisan
  29. Peter Bruenker
  30. Christian Klein
  31. Marina Bacac
  32. Nikolce Gjorevski
  33. Lauriane Cabon
(2021)
Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies
eLife 10:e67106.
https://doi.org/10.7554/eLife.67106

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