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.

抗体介导的主要组织相容性复合物 (MHC) 分子或 MHC I 类分子的调节可以构成一种有效的免疫治疗方法。我们描述了人类 MHC I 类样分子 CD1d 特异性的单域抗体 (VHH) 如何调节 CD1d 限制性 T 细胞的功能，以及一个 VHH (1D12) 如何特异性诱导强 I 型自然杀伤 T (NKT) ) 细胞活化。VHH1D12-CD1d(α-GalCer)-NKT T 细胞受体 (TCR) 复合物的晶体结构显示 VHH1D12 同时接触 CD1d 和 I 型 NKT TCR，从而通过内在的双特异性稳定这种相互作用。这导致 I 型 NKT 细胞介导的体外抗肿瘤活性大大增强，包括多发性骨髓瘤和急性髓性白血病患者衍生的骨髓样本，以及体内模型。