{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T03:27:50Z","timestamp":1792207670746,"version":"4.4.0"},"posted":{"date-parts":[[2026,5,19]]},"group-title":"Immunology","reference-count":59,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>T cell receptors (TCRs) are critical for immune surveillance and successful adaptive immune response against foreign antigens. TCRs drive this key arm of the immune system through recognition of peptide epitopes presented on MHC complexes. However, they are limited due to their stochastic nature and generation via genetic recombination. In silico design of functional TCRs that target defined peptide epitopes would be of considerable utility but has up until now been unsuccessful. Here, we develop an artificial intelligence (AI)-powered approach using a hybrid physics-based simulation and generative AI that successfully engineers TCRs against defined epitopes presented by MHC-I. We use this approach to design TCRs against two cancer antigens, a HERC1 neoantigen and an immunogenic neoepitope in mutant EGFR. We engineer multiple TCRs against the HERC1 neoantigen which activate T cells in response to exposure to peptide-MHC I and kill cancer cells more effectively than a patient-derived TCR. In addition, we used generative AI to design functional TCRs that target the EGFR T790M neoantigen, engineering greater specificity against the mutant sequence. We present an AI-based approach to TCR design with broad utility for efforts to engineer TCRs and for the development of new cell therapies.<\/jats:p>\n                <jats:sec>\n                  <jats:title>One sentence summary<\/jats:title>\n                  <jats:p>Artificial intelligence-based approach enables the directed engineering of functional TCRs with enhanced features that target cancer neoantigens.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.15.725176","type":"posted-content","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T16:15:24Z","timestamp":1779207324000},"source":"Crossref","is-referenced-by-count":1,"title":["Engineering Endogenous T Cell Receptors to Recognize Cancer Neoantigens Using a Hybrid Physics-AI Approach"],"prefix":"10.64898","author":[{"given":"Jeffrey K.","family":"Weber","sequence":"first","affiliation":[{"name":"IBM Thomas J. Watson Research Center, 1101 Kitchawan Rd. Yorktown Heights, NY 10598, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gyanu","family":"Parajuli","sequence":"additional","affiliation":[{"name":"Dept. of Cancer Sciences and Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Wang","sequence":"additional","affiliation":[{"name":"Dept. of Cancer Sciences and Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA"},{"name":"Case Western School of Medicine, Cleveland, OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vadim","family":"Ratner","sequence":"additional","affiliation":[{"name":"IBM Research-Israel, IBM Research, Haifa, 3498825, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxiao","family":"Ma","sequence":"additional","affiliation":[{"name":"Dept. of Cancer Sciences and Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoel","family":"Shoshan","sequence":"additional","affiliation":[{"name":"IBM Research-Israel, IBM Research, Haifa, 3498825, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leili","family":"Zhang","sequence":"additional","affiliation":[{"name":"IBM Thomas J. Watson Research Center, 1101 Kitchawan Rd. Yorktown Heights, NY 10598, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph A.","family":"Morrone","sequence":"additional","affiliation":[{"name":"IBM Thomas J. Watson Research Center, 1101 Kitchawan Rd. Yorktown Heights, NY 10598, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moshiko","family":"Raboh","sequence":"additional","affiliation":[{"name":"IBM Research-Israel, IBM Research, Haifa, 3498825, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Efrat","family":"Hexter","sequence":"additional","affiliation":[{"name":"IBM Research-Israel, IBM Research, Haifa, 3498825, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prerana","family":"Parthasarathy","sequence":"additional","affiliation":[{"name":"Dept. of Cancer Sciences and Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Pavicic","sequence":"additional","affiliation":[{"name":"Dept. of Cancer Sciences and Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Gaughan","sequence":"additional","affiliation":[{"name":"Dept. of Cancer Sciences and Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir","family":"Makarov","sequence":"additional","affiliation":[{"name":"Dept. of Cancer Sciences and Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence","family":"Chu","sequence":"additional","affiliation":[{"name":"Dept. of Cancer Sciences and Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suheyla","family":"Hasgur","sequence":"additional","affiliation":[{"name":"Dept. of Cancer Sciences and Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Juric","sequence":"additional","affiliation":[{"name":"Dept. of Cancer Sciences and Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. Marcela","family":"Diaz-Montero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raghvendra","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Dept. of Cancer Sciences and Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A.","family":"Knauf","sequence":"additional","affiliation":[{"name":"Dept. of Cancer Sciences and Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khaled A.","family":"Hassan","sequence":"additional","affiliation":[{"name":"Cancer Institute, Cleveland Clinic, Cleveland, OH 44195 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy D.","family":"Cornell","sequence":"additional","affiliation":[{"name":"IBM Thomas J. Watson Research Center, 1101 Kitchawan Rd. 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Motmaen et al., Targeting peptide-MHC complexes with designed T cell receptors and antibodies. bioRxiv, (2025).","DOI":"10.1101\/2025.11.19.689381"},{"key":"2026052202251187000_2026.05.15.725176v1.14","article-title":"Evaluating Zero-Shot Scoring for In Vitro Antibody Binding Prediction with Experimental Validation","year":"2023","journal-title":"arXiv preprint"},{"key":"2026052202251187000_2026.05.15.725176v1.15","unstructured":"N. Bio , S. Biswas , De novo design of epitope-specific antibodies against soluble and multipass membrane proteins with high specificity, developability, and function. bioRxiv, 2025.2001.2021.633066 (2025)."},{"key":"2026052202251187000_2026.05.15.725176v1.16","unstructured":"Y. Bang et al., Precise, Specific, and Sensitive De Novo Antibody Design Across Multiple Cases. bioRxiv, 2025.2003.2009.642274 (2025)."},{"key":"2026052202251187000_2026.05.15.725176v1.17","unstructured":"N. R. 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