Journal article

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, Jerome Le Nours, Richard WJ Groen, Jana Vree, Scott JJ Reddiex, Sergio M Quinones-Parra, Stewart K Richardson, Amy R Howell, Sonja Zweegman, Dale I Godfrey, Tanja D de Gruijl, Jamie Rossjohn, Hans J van der Vliet

NATURE CANCER | SPRINGERNATURE | Published : 2020

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 cel..

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Grants

Awarded by CCA-VICI grant from the VU University Medical Center


Awarded by Worldwide Cancer Research


Awarded by National Health and Medical Research Council of Australia (NHMRC)


Awarded by Australian Research Council (ARC)


Awarded by NHMRC


Awarded by National Institutes of Health


Awarded by ARC


Funding Acknowledgements

This work was supported by CCA-VICI grant no. 2000483 from the VU University Medical Center, grant no. 140343 from Worldwide Cancer Research, funding from LAVA Therapeutics (R.L., J.V. and H.J.V.), the National Health and Medical Research Council of Australia (NHMRC; grant nos. 1113293 and 1140126), the Australian Research Council (ARC; grant no. CE140100011) and the Cancer Council of Victoria (J.R., D.I.G.). S.G. is supported by an NHMRC Senior Research Fellowship (no. GNT#1159272). A.R.H. is supported by National Institutes of Health (grant no. R01 GM111849). D.I.G. is supported by an NHMRC Senior Principal Research Fellowship (no. 1117766). A.P.U. is supported by an ARC Future Fellowship (no. FT140100278). J.L.N is supported by an ARC Future Fellowship (no. FT160100074). J.R. is supported by an ARC Laureate Fellowship (no. FL160100049). We thank the Monash Macromolecular Crystallization Facility staff for assistance with crystallization, the Australian Synchrotron for assistance with data collection, the University of Melbourne, Department of Microbiology and Immunology Flow Cytometry facility for flow cytometry support, L. Smit and K. K. Sivaramanand for assistance and P.W.H.I. Parren for comments.