Lameris and Shahine et al. showed that the single domain anti-CD1d antibody VHH1D12 has bispecific properties and stabilizes human type I semi-invariant NKT-TCR-CD1d interaction. VHH1D12 promoted type I NKT cell reactivity towards weak agonistic antigens and blocked pro-tumor type II NKT cells binding to CD1d. In a coculture system, VHH1D12 induced type I NKT cell-mediated cytokine secretion (IFNγ, TNF, IL-2) and cytotoxicity towards CD1d-expressing tumor cells and both MM and AML patient bone marrow samples. In a MM mouse model, VHH1D12 enhanced type I NKT cell-mediated tumor control and prolonged survival.
Contributed by Shishir Pant
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 stabiliz- ing 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.
Author Info: (1) Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam, the Netherlands. (2) Infection and Immunity Program and Departm
Author Info: (1) Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam, the Netherlands. (2) Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. (3) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia. (4) Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Haematology, Cancer Center Amsterdam, Amsterdam, the Netherlands. (5) Department of Chemistry, University of Connecticut, Storrs, CT, USA. (6) Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne, Victoria, Australia. (7) Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia. (8) Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.
(9) LAVA Therapeutics, Utrecht, the Netherlands. (10) Present address: Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia. (11) Present address: Division of Biological Sciences, Department of Molecular Biology, University of California, San Diego, La Jolla, CA, USA. (12) These authors contributed equally: Roeland Lameris, Adam Shahine. (13) These authors jointly supervised this work: Jamie Rossjohn, Hans J. van der Vliet. e-mail: jamie.rossjohn@monash.edu; jj.vandervliet@amsterdamumc.nl
