A general platform for targeting MHC-II antigens via a single loop

Du, H.; Liu, J.; Jude, K. M.; Yang, X.; Li, Y.; Bell, B.; Yang, H.; Kassardjian, A.; Mobedi, A.; Parekh, U.; Sperberg, A.; Julien, J.-P.; Mellins, E.; Garcia, K. C.; Huang, P.

doi:10.1101/2024.01.26.577489

bioRxiv · 10.1101/2024.01.26.577489

A general platform for targeting MHC-II antigens via a single loop

Du, H.·Liu, J.·Jude, K. M.·Yang, X.·Li, Y.·Bell, B.·Yang, H.·Kassardjian, A.·Mobedi, A.·Parekh, U.·Sperberg, A.·Julien, J.-P.·Mellins, E.·Garcia, K. C.·Huang, P.

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Abstract

Class-II major histocompatibility complexes (MHC-IIs) are central to the communications between CD4+ T cells and antigen presenting cells (APCs), but intrinsic structural features associated with MHC-II make it difficult to develop a general targeting system with high affinity and antigen specificity. Here, we introduce a protein platform, Targeted Recognition of Antigen-MHC Complex Reporter for MHC-II (TRACeR-II), to enable the rapid development of peptide-specific MHC-II binders. TRACeR-II has a small helical bundle scaffold and uses an unconventional mechanism to recognize antigens via a single loop. This unique antigen-recognition mechanism renders this platform highly versatile and amenable to direct structural modeling of the interactions with the antigen. We demonstrate that TRACeR-II binders can be rapidly evolved across multiple alleles, while computational protein design can produce specific binding sequences for a SARS-CoV-2 peptide of unknown complex structure. TRACeR-II sheds light on a simple and straightforward approach to address the MHC peptide targeting challenge, without relying on combinatorial selection on complementarity determining region (CDR) loops. It presents a promising basis for further exploration in immune response modulation as well as a broad range of theragnostic applications.

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Du, H., Liu, J., Jude, K. M., Yang, X., Li, Y., Bell, B., Yang, H., Kassardjian, A., Mobedi, A., Parekh, U., Sperberg, A., Julien, J.-P., Mellins, E., Garcia, K. C., Huang, P.. 2024-01-30. A general platform for targeting MHC-II antigens via a single loop. https://doi.org/10.1101/2024.01.26.577489

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