A single-domain bispecific antibody targeting CD1d and the NKT T-cell receptor induces a potent antitumor response

Roeland Lameris, Adam Shahine, Daniel G. Pellicci, Adam P. Uldrich, Stephanie Gras, Jérôme Le Nours, Richard W.J. Groen, Jana Vree, Scott J.J. Reddiex, Sergio M. Quiñones-Parra, Stewart K. Richardson, Amy R. Howell, Sonja Zweegman, Dale I. Godfrey, Tanja D. de Gruijl, Jamie Rossjohn, Hans J. van der Vliet

Research output: Contribution to journalArticleResearchpeer-review

30 Citations (Scopus)

Abstract

Antibody-mediated modulation of major histocompatibility complex (MHC) molecules, or MHC class I-like molecules, could constitute an effective immunotherapeutic approach. We describe how single-domain antibodies (VHH), specific for the human MHC class I-like molecule CD1d, can modulate the function of CD1d-restricted T cells and how one VHH (1D12) specifically induced strong type I natural killer T (NKT) cell activation. The crystal structure of the VHH1D12-CD1d(α-GalCer)-NKT T-cell receptor (TCR) complex revealed that VHH1D12 simultaneously contacted CD1d and the type I NKT TCR, thereby stabilizing this interaction through intrinsic bispecificity. This led to greatly enhanced type I NKT cell-mediated antitumor activity in in vitro, including multiple myeloma and acute myeloid leukemia patient-derived bone marrow samples, and in vivo models. Our findings underscore the versatility of VHH molecules in targeting composite epitopes, in this case consisting of a complexed monomorphic antigen-presenting molecule and an invariant TCR, and represent a generalizable antitumor approach.

Original languageEnglish
Pages (from-to)1054-1065
Number of pages12
JournalNature Cancer
Volume1
Issue number11
DOIs
Publication statusPublished - Nov 2020

Keywords

  • antibody therapy
  • cancer
  • cancer immunotherapy
  • immunotherapy
  • x-ray crystallography
  • ARC Centre of Excellence in Advanced Molecular Imaging

    Whisstock, J. (Primary Chief Investigator (PCI)), Abbey, B. (Chief Investigator (CI)), Nugent, K. A. (Chief Investigator (CI)), Quiney, H. M. (Chief Investigator (CI)), Godfrey, D. I. (Chief Investigator (CI)), Heath, W. (Chief Investigator (CI)), Fairlie, D. P. (Chief Investigator (CI)), Chapman, H. (Partner Investigator (PI)), Peele, A. (Partner Investigator (PI)), Davey, J. (Partner Investigator (PI)) & Wittmann, A. (Project Manager)

    30/06/1431/03/21

    Project: Research

Cite this