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

Lameris, Roeland, Shahine, Adam, Pellicci, Daniel G., Uldrich, Adam P., Gras, Stephanie, Le Nours, Jérôme, Groen, Richard W. J., Vree, Jana, Reddiex, Scott J. J., Quiñones-Parra, Sergio M., Richardson, Stewart K., Howell, Amy R., Zweegman, Sonja, Godfrey, Dale I., de Gruijl, Tanja D., Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522 and van der Vliet, Hans J. 2020. A single-domain bispecific antibody targeting CD1d and the NKT T-cell receptor induces a potent antitumor response. Nature Cancer 1 (11) , pp. 1054-1065. 10.1038/s43018-020-00111-6

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Publisher:	Nature Research
ISSN:	2662-1347
Date of Acceptance:	5 August 2020
Last Modified:	10 Nov 2022 11:23
URI:	https://orca.cardiff.ac.uk/id/eprint/150332

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