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. 2023 Aug 22;8:126. doi: 10.1038/s41541-023-00713-y

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — Potential off-target reactivity of candidate therapeutic TCRs is first mapped using a peptide library containing the intended epitope with all possible single AA substitutions (Step 1). The TCR fingerprint is next screened against the human proteome using a computer algorithm. This bioinformatic search identifies potential cross-reactive epitopes containing one or any combination of multiple allowed AA substitutions (Step 2), which are then synthesized and tested for TCR-recognition in Step 3. Cleavage of candidate epitopes is studied by probing TCR-reactivity against target cells electroporated with mRNA constructs encoding 30-mer peptides containing the candidate cross-recognized epitope in the middle (Step 4). To evaluate if the candidate off-target epitope is processed and presented in a physiological setting, TCR-reactivity is probed against cell lines naturally expressing confirmed high levels of proteins containing the candidate off-target epitope (Step 5). The sum of preclinical data accumulated from (i) the off-target reactivity pipeline, (ii) assessment of potential recognition of unintended HLA-alleles and (iii) in vivo efficacy studies form the basis for an informed decision regarding clinical translation. Figure 1 is created by Ellen Tenstad, Science Shaped.