Year: 2026
Type: article
Abstract: T cell receptor mimic (TCRm) antibodies and nanobodies that specifically bind peptide-HLA complexes have great therapeutic potential, as they can target polymorphic HLA on tumour cells furnishing peptides derived from tumour-associated antigens. MR1 is an MHC class-I-like molecule that exhibits limited polymorphism that binds and presents conserved metabolites, such as 5-OP-RU, derived from microbial riboflavin biosynthesis. Whether antibodies targeting such MR1-5-OP-RU complexes can be generated remains unclear. Using yeast display technology and in vitro affinity maturation, a nanobody with high affinity and fine specificity toward MR1-5-OP-RU complex was generated. These nanobodies bind both mouse and human MR1-5-OP-RU and inhibited MAIT cell responses to 5-OP-RU in vitro and in vivo demonstrating therapeutic potential. Moreover, we provide a molecular basis underpinning the fine specificity of these nanobodies, solving the crystal structures of MR1 in complex with either 5-OP-RU or Ac-6-FP. Here, the nanobody co-bound MR1 and 5-OP-RU, akin to a TCRm antibody. Moreover, we engineer bispecific antibodies targeting both MR1-5-OP-RU and CD3, that drive broad T cell killing of bacterially-infected cells as well as tumour cells treated with 5-OP-RU, thereby providing proof-of-principle for targeting the MR1 molecule with with TCRm-based nanobodies. One Sentence Summary We report the development of a nanobody targeting MR1-5-OP-RU complex and demonstrate its utility to modulate MAIT cells responses, and as a bispecific engager.
Source: Science Immunology
Authors: Hisham S. Hussain, Samuel J. Redmond, Wael Awad, Calvin Xu, Caroline Soliman, Huimeng Wang, Yuyang Zhang, Lisa Ciacchi, Alexis P. Gonzalez, Jeffrey Y. W. Mak, David P. Fairlie, James McCluskey, Alexandra J. Corbett, Adam P. Uldrich, Jamie Rossjohn, Dale I. Godfrey, Hui-Fern Koay, Nicholas A. Gherardin
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Targeting vitamin-reactive T cells for enhanced immunity, A molecular investigation into T cell antigen receptor function and dysfunction in humans, ARC Centre of Excellence for Innovations in Peptide and Protein Science, A molecular investigation into metabolite-mediated T cell immunity, Modulating protein-protein interactions in disease, Elucidating the genesis of MAIT cell-mediated immunity, Harnessing MAIT cells as the next frontier of solid tumour immunotherapy, Unconventional T cells in health and disease, An investigation into metabolite-mediated immunity, Exploiting the unique functions of MAIT cells to drive the rational design of new vaccines and immunotherapies, Understanding and Harnessing gamma-delta T cell-mediated tumour Immunity, Unconventional T cells: Fundamental biology and therapeutic potential, G8422245163, G9000373665
OpenAlex ID: W7214293960