Targeting peptide antigens using a multiallelic MHC I-binding system

• Published in: Nature biotechnology 2024-12
• Main Authors: Du, Haotian, Mallik, Leena, Hwang, Daniel, Sun, Yi, Kaku, Chengzi, Hoces, Daniel, Sun, Shirley M, Ghinnagow, Reem, Carro, Stephen D, Phan, Hoang Anh T, Gupta, Sagar, Blackson, Wyatt, Lee, Hyejin, Choe, Christian A, Dersh, Devin, Liu, Jingjia, Bell, Braxton, Yang, Hongli, Papadaki, Georgia F, Young, Michael C, Zhou, Emily, El Nesr, Gina, Goli, Kimia Dasteh, Eisenlohr, Laurence C, Minn, Andy J, Hernandez-Lopez, Rogelio A, Jardine, Joseph G, Sgourakis, Nikolaos G, Huang, Po-Ssu
• Format: Article
• Language: English
• ISSN: 1087-0156; 1546-1696; 1546-1696
• DOI: 10.1038/s41587-024-02505-8

Identifying highly specific T cell receptors (TCRs) or antibodies against epitopic peptides presented by class I major histocompatibility complex (MHC I) proteins remains a bottleneck in the development of targeted therapeutics. Here, we introduce targeted recognition of antigen-MHC complex reporter for MHC I (TRACeR-I), a generalizable platform for targeting peptides on polymorphic HLA-A*, HLA-B* and HLA-C* allotypes while overcoming the cross-reactivity challenges of TCRs. Our TRACeR-MHC I co-crystal structure reveals a unique antigen recognition mechanism, with TRACeR forming extensive contacts across the entire peptide length to confer single-residue specificity at the accessible positions. We demonstrate rapid screening of TRACeR-I against a panel of disease-relevant HLAs with peptides derived from human viruses (human immunodeficiency virus, Epstein-Barr virus and severe acute respiratory syndrome coronavirus 2), and oncoproteins (Kirsten rat sarcoma virus, paired-like homeobox 2b and New York esophageal squamous cell carcinoma 1). TRACeR-based bispecific T cell engagers and chimeric antigen receptor T cells exhibit on-target killing of tumor cells with high efficacy in the low nanomolar range. Our platform empowers the development of broadly applicable MHC I-targeting molecules for research, diagnostic and therapeutic applications.