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.