Whereas one (VHH1D22) specifically blocked type I NKT cell reactivity by binding directly at the NKT T cell receptor (TCR)-CD1d interface, another (VHH1D12) specifically induced strong type I NKT-cell activation and simultaneously blocked the activity of other CD1d-restricted T cells.
The crystal structure of the VHH1D12-CD1d-α-GalCer-type I NKT TCR complex revealed that VHH1D12 simultaneously contacted CD1d and the type I NKT TCR, thereby stabilising this interaction through intrinsic bi-specificity. This led to greatly enhanced type I NKT cell mediated anti-tumour activity both in in vitro models (including myeloma patient-derived bone marrow samples) and in an in vivo multiple myeloma model.
These findings demonstrate the feasibility of generating antibodies that modulate the function of antigen-presenting molecules and the specific T cells with which they interact, and underscores the versatility of VHH molecules in terms of targeting composite epitopes, in this case consisting of a complexed monomorphic antigen-presenting molecule and an invariant TCR.
This paper was accepted for publication in Nature Cancer.