Targeting peptide antigens using a multiallelic MHC I-binding system

Haotian Du; Leena Mallik; Daniel Hwang; Yi Sun; Chengzi Kaku; Daniel Hoces; Shirley M Sun; Reem Ghinnagow; Stephen D Carro; Hoang Anh T Phan; Sagar Gupta; Wyatt Blackson; Hyejin Lee; Christian A Choe; Devin Dersh; Jingjia Liu; Braxton Bell; Hongli Yang; Georgia F Papadaki; Michael C Young; Emily Zhou; Gina El Nesr; Kimia Dasteh Goli; Laurence C Eisenlohr; Andy J Minn; Rogelio A Hernandez-Lopez; Joseph G Jardine; Nikolaos G Sgourakis; Po-Ssu Huang

doi:10.1038/s41587-024-02505-8

Targeting peptide antigens using a multiallelic MHC I-binding system

Nat Biotechnol. 2024 Dec 13. doi: 10.1038/s41587-024-02505-8. Online ahead of print.

Authors

Haotian Du¹, Leena Mallik^{2

3}, Daniel Hwang^{2

3}, Yi Sun^{2

3}, Chengzi Kaku⁴, Daniel Hoces^{5

6}, Shirley M Sun^{2

7}, Reem Ghinnagow⁸, Stephen D Carro⁹, Hoang Anh T Phan^{2

3}, Sagar Gupta^{2

3}, Wyatt Blackson¹⁰, Hyejin Lee⁵, Christian A Choe⁵, Devin Dersh⁸, Jingjia Liu⁵, Braxton Bell¹, Hongli Yang⁵, Georgia F Papadaki^{2

3}, Michael C Young^{2

3}, Emily Zhou⁴, Gina El Nesr¹¹, Kimia Dasteh Goli^{2

3}, Laurence C Eisenlohr⁹, Andy J Minn⁸, Rogelio A Hernandez-Lopez^{5

6

12

13}, Joseph G Jardine⁴, Nikolaos G Sgourakis^{14

15}, Po-Ssu Huang^{16

17

18}

Affiliations

¹ Department of Chemistry, Stanford University, Stanford, CA, USA.
² Center for Computational and Genomic Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
³ Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA, USA.
⁵ Department of Bioengineering, Stanford University, Stanford, CA, USA.
⁶ Department of Genetics, Stanford University, Stanford, CA, USA.
⁷ Cancer Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁸ Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁹ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰ Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
¹¹ Biophysics Program, Stanford University, Stanford, CA, USA.
¹² Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
¹³ Chan-Zuckerberg Biohub, San Francisco, CA, USA.
¹⁴ Center for Computational and Genomic Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA. [email protected].
¹⁵ Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
¹⁶ Department of Chemistry, Stanford University, Stanford, CA, USA. [email protected].
¹⁷ Department of Bioengineering, Stanford University, Stanford, CA, USA. [email protected].
¹⁸ Biophysics Program, Stanford University, Stanford, CA, USA. [email protected].

PMID: 39672954
DOI: 10.1038/s41587-024-02505-8

Abstract

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.

Abstract

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