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.
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.
Genome-wide transcriptome profiling of human organoids, colon intestine-chip and human alveolus-chips using RNA-seqNCBI Gene Expression Omnibus, GSE175821.
The authors declare that there was no funding for this work.
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 184.108.40.206-2532.0-10-16). We have complied with all relevant ethical guidelines and regulations.
- Ping-Chih Ho, Ludwig Institute for Cancer Research, Switzerland
© 2021, Kerns et al.
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