Bispecific T-cell engagers (BiTEs) bring together tumour cells and cytotoxic T cells by binding to specific cell-surface tumour antigens and T-cell receptors, and have been clinically successful for the treatment of B-cell malignancies. Here we show that a BiTE–sialidase fusion protein enhances the susceptibility of solid tumours to BiTE-mediated cytolysis of tumour cells via targeted desialylation—that is, the removal of terminal sialic acid residues on glycans—at the BiTE-induced T-cell–tumour-cell interface. In xenograft and syngeneic mouse models of leukaemia and of melanoma and breast cancer, and compared with the parental BiTE molecules, targeted desialylation via the BiTE–sialidase fusion proteins enhanced the formation of immunological synapses, T-cell activation and T-cell-mediated tumour-cell cytolysis in the presence of the target antigen. The targeted desialylation of tumour cells may enhance the potency of therapies relying on T-cell engagers.

双特异性 T 细胞接合器 （BiTE） 通过与特定的细胞表面肿瘤抗原和 T 细胞受体结合，将肿瘤细胞和细胞毒性 T 细胞结合在一起，并在临床上成功治疗 B 细胞恶性肿瘤。在这里，我们表明 BiTE-唾液酸酶融合蛋白通过在 BiTE 诱导的 T 细胞-肿瘤-细胞界面处通过靶向去唾液酸化（即去除聚糖上的末端唾液酸残基）增强了实体瘤对 BiTE 介导的肿瘤细胞细胞溶细胞的敏感性。在白血病、黑色素瘤和乳腺癌的异种移植和同基因小鼠模型中，与亲本 BiTE 分子相比，在靶抗原存在下，通过 BiTE-唾液酸酶融合蛋白的靶向去唾液酸化增强了免疫突触的形成、T 细胞活化和 T 细胞介导的肿瘤细胞溶解。肿瘤细胞的靶向去唾液酸化可能会增强依赖于 T 细胞接合器的治疗的有效性。