The broader clinical use of bispecific T cell engagers for inducing anti-tumour toxicity is hindered by their on-target off-tumour toxicity and the associated neurotoxicity and cytokine-release syndrome. Here we show that the off-tumour toxicity of a supramolecular bispecific T cell engager binding to the T cell co-receptor CD3 and to the human epidermal growth factor receptor 2 on breast tumour cells can be halted by disengaging the T cells from the tumour cells via the infusion of the small-molecule drug amantadine, which disassembles the supramolecular aggregate. In mice bearing human epidermal growth factor receptor 2-expressing tumours and with a human immune system, high intravenous doses of such a ‘switchable T cell nanoengager’ elicited strong tumour-specific adaptive immune responses that prevented tumour relapse, while the infusion of amantadine restricted off-tumour toxicity, cytokine-release syndrome and neurotoxicity. Supramolecular chemistry may be further leveraged to control the anti-tumour activity and off-tumour toxicity of bispecific antibodies.

双特异性 T 细胞接合剂诱导抗肿瘤毒性的更广泛临床应用受到其靶向非肿瘤毒性以及相关的神经毒性和细胞因子释放综合征的阻碍。在这里，我们表明，与乳腺肿瘤细胞上的 T 细胞辅助受体 CD3 和人表皮生长因子受体 2 结合的超分子双特异性 T 细胞接合剂的肿瘤外毒性可以通过使 T 细胞与肿瘤细胞脱离来停止。通过注入小分子药物金刚烷胺，分解超分子聚集体。在携带人类表皮生长因子受体 2 表达肿瘤且具有人类免疫系统的小鼠中，高静脉注射剂量的这种“可切换 T 细胞纳米接合剂”引发了强烈的肿瘤特异性适应性免疫反应，从而防止肿瘤复发，而金刚烷胺的输注则限制了肿瘤的复发。肿瘤外毒性、细胞因子释放综合征和神经毒性。超分子化学可进一步用于控制双特异性抗体的抗肿瘤活性和肿瘤外毒性。