Poster Presentation Lorne Infection and Immunity 2022

A bi-specific VHH antibody targeting the CD1d-Natural Killer T cell axis that displays potent anti-tumour immunity. (#207)

Roeland Lameris 1 , Adam Shahine 2 3 , Daniel G Pellicci 4 , Adam Uldrich 4 , Stephanie Gras 3 , Jerome Le Nours 3 , Richard W J Groen 1 , Jana Vree 1 , Scott J J Reddiex 4 , Sergio M Quiñones-Parra 5 , Sonja Zweegman 1 , Dale Godfrey 4 , Tanja D de Gruijl 1 , Jamie Rossjohn 2 3 6 , Hans J van der Vliet 1 7
  1. Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
  2. Australian Research Council Center of Excellence in Advanced Molecular Imaging, Melbourne
  3. Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
  4. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia
  5. Division of Biological Sciences, Department of Molecular Biology, University of California, San Diego, California, USA
  6. Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales, UK
  7. Lava Therapeutics, Utrecht, The Netherlands

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.

 

  1. Lameris R, SHAHINE A., et al. (2020) A single-domain bispecific antibody targeting CD1d and the NKT T-cell receptor induces a potent antitumor response.” Nat. Cancer. 1-2