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

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21 Citations (Scopus)


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
Issue number11
Publication statusPublished - Nov 2020


  • antibody therapy
  • cancer
  • cancer immunotherapy
  • immunotherapy
  • x-ray crystallography

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