A general system for targeting MHC class II-antigen complex via a single adaptable loop

Haotian Du; Jingjia Liu; Kevin M Jude; Xinbo Yang; Ying Li; Braxton Bell; Hongli Yang; Audrey Kassardjian; Wyatt Blackson; Ali Mobedi; Udit Parekh; R Andres Parra Sperberg; Jean-Philippe Julien; Elizabeth D Mellins; K Christopher Garcia; Po-Ssu Huang

doi:10.1038/s41587-024-02466-y

A general system for targeting MHC class II-antigen complex via a single adaptable loop

Nat Biotechnol. 2024 Dec 13. doi: 10.1038/s41587-024-02466-y. Online ahead of print.

Authors

Haotian Du^#¹, Jingjia Liu^#², Kevin M Jude³, Xinbo Yang³, Ying Li^{4

5}, Braxton Bell¹, Hongli Yang², Audrey Kassardjian^{6

7}, Wyatt Blackson⁸, Ali Mobedi², Udit Parekh², R Andres Parra Sperberg², Jean-Philippe Julien^{6

7

9}, Elizabeth D Mellins^{4

5}, K Christopher Garcia^{3

10}, Po-Ssu Huang¹¹

Affiliations

¹ Department of Chemistry, Stanford University, Stanford, CA, USA.
² Department of Bioengineering, Stanford University, Stanford, CA, USA.
³ Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Department of Pediatrics, Divisions of Human Gene Therapy and Allergy, Immunology & Rheumatology, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Stanford Program in Immunology, Stanford University School of Medicine, Stanford, CA, USA.
⁶ Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
⁷ Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
⁸ Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
⁹ Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
¹¹ Department of Bioengineering, Stanford University, Stanford, CA, USA. possu@stanford.edu.

^# Contributed equally.

PMID: 39672953
DOI: 10.1038/s41587-024-02466-y

Abstract

Major histocompatibility complex class II (MHCII) bound to a peptide antigen mediates interactions between CD4⁺ T cells and antigen-presenting cells. Targeting peptide-MHCII with T cell antigen receptors (TCRs) and TCR-like antibodies has shown promise for autoimmune diseases and microbiome tolerance. To develop a general targeting approach, we introduce targeted recognition of antigen-MHC complex reporter for MHCII (TRACeR-II) for the rapid development of peptide-specific MHCII binders. TRACeR-II binders have a small helical bundle scaffold and use a single loop to recognize peptide-MHCII, which offers versatility and enables structural modeling of the interactions to target MHCII antigens. We demonstrate rapid generation of TRACeR-II binders to multiple molecules with affinities in the low-nanomolar to low-micromolar range, comparable to best-in-class TCRs and antibodies. Through computational protein design, we created specific binding sequences in silico from only the sequence of a severe acute respiratory syndrome coronavirus 2 peptide. TRACeR-II provides a straightforward approach to target antigen-MHCII without relying on combinatorial selection on complementarity-determining region loops.

Abstract

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