Targeting peptide antigens using a multiallelic MHC I-binding system
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.
Authors
- Stephen D. Carro (ORCID: https://orcid.org/0000-0003-3756-1429)
- Reem Ghinnagow (ORCID: https://orcid.org/0009-0002-8844-8506)
- Hoang Anh T. Phan (ORCID: https://orcid.org/0000-0001-6488-0404)
- Chengzi I. Kaku (ORCID: https://orcid.org/0000-0002-9854-8351)
- Daniel Hoces (ORCID: https://orcid.org/0000-0002-1451-5166)
- Po‐Ssu Huang (ORCID: https://orcid.org/0000-0002-7948-2895)
- Hyejin Lee (ORCID: https://orcid.org/0000-0001-5279-340X)
- Haotian Du
- Nikolaos G. Sgourakis (ORCID: https://orcid.org/0000-0003-3655-3902)
- Emily Zhou (ORCID: https://orcid.org/0000-0002-9194-7042)
- Joseph G. Jardine (ORCID: https://orcid.org/0000-0001-8951-1074)
- Gina El Nesr (ORCID: https://orcid.org/0000-0003-4857-9464)
- Jingjia Liu (ORCID: https://orcid.org/0000-0002-6038-593X)
- Daniel Hwang (ORCID: https://orcid.org/0000-0002-6071-8271)
- Laurence C. Eisenlohr
- Leena Mallik (ORCID: https://orcid.org/0000-0002-5979-7494)
- Wyatt Blackson (ORCID: https://orcid.org/0000-0002-2452-5915)
- Christian A. Choe (ORCID: https://orcid.org/0000-0001-8871-9682)
- Kimia Dasteh Goli (ORCID: https://orcid.org/0009-0005-6921-655X)
- Devin Dersh (ORCID: https://orcid.org/0000-0002-3763-4192)
- Yi Sun (ORCID: https://orcid.org/0000-0002-7821-4346)
- Georgia Papadaki (ORCID: https://orcid.org/0000-0003-0630-2248)
- Rogelio A. Hernández‐López (ORCID: https://orcid.org/0000-0003-3968-4908)
- Andy J. Minn (ORCID: https://orcid.org/0000-0003-1418-0906)
- Michael C. Young (ORCID: https://orcid.org/0000-0002-8420-2149)
- Sagar Gupta (ORCID: https://orcid.org/0009-0007-0427-2635)
- Hongli Yang
- Shirley M. Sun (ORCID: https://orcid.org/0000-0002-4875-0033)
- Braxton Bell
Institutions
- Scripps Research Institute (US)
- Children's Hospital of Philadelphia (US)
- Chan Zuckerberg Initiative (United States) (US)
- University of Pennsylvania (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Biotechnology
- Published
- 2024-12-13
- DOI
- https://doi.org/10.1038/s41587-024-02505-8
- Citations
- 21
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- article
- Field-Weighted Citation Impact
- 5.05
Funders
- National Science Foundation
- U.S. Department of Energy
- American Cancer Society
- Stanford University
- Children's Hospital of Philadelphia
- Mark Foundation For Cancer Research
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institutes of Health
- Office of Science
- School of Medicine, Stanford University
- University of California, San Francisco
- Stanford Bio-X
- National Institute of General Medical Sciences
- National Institute of Allergy and Infectious Diseases
- Biological and Environmental Research