The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba QLD 4102, Australia.
Cell Biology and Molecular Medicine Division, Institute for Molecular Bioscience, University of Queensland, St Lucia QLD 4072, Australia; Australia Centre for Microscopy and Microanalysis, University of Queensland, St Lucia QLD 4072, Australia.
Cell. 2020 Mar 5;180(5):895-914.e27. doi: 10.1016/j.cell.2020.02.019.
A safe and controlled manipulation of endocytosis in vivo may have disruptive therapeutic potential. Here, we demonstrate that the anti-emetic/anti-psychotic prochlorperazine can be repurposed to reversibly inhibit the in vivo endocytosis of membrane proteins targeted by therapeutic monoclonal antibodies, as directly demonstrated by our human tumor ex vivo assay. Temporary endocytosis inhibition results in enhanced target availability and improved efficiency of natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC), a mediator of clinical responses induced by IgG1 antibodies, demonstrated here for cetuximab, trastuzumab, and avelumab. Extensive analysis of downstream signaling pathways ruled out on-target toxicities. By overcoming the heterogeneity of drug target availability that frequently characterizes poorly responsive or resistant tumors, clinical application of reversible endocytosis inhibition may considerably improve the clinical benefit of ADCC-mediating therapeutic antibodies.
在体内安全可控地操纵内吞作用可能具有突破性的治疗潜力。在这里，我们证明了止吐/抗精神病药丙氯拉嗪可以被重新用于可逆地抑制治疗性单克隆抗体靶向的膜蛋白的内吞作用，正如我们的人体肿瘤离体实验直接证明的那样。暂时的内吞作用抑制导致靶标可用性增加和自然杀伤细胞介导的抗体依赖性细胞毒性（ADCC）效率提高，ADCC 是 IgG1 抗体诱导的临床反应的介导者，在这里证明了用于西妥昔单抗、曲妥珠单抗和avelumab 的情况。对下游信号通路的广泛分析排除了靶毒性。通过克服经常表现为反应差或耐药肿瘤的药物靶标可用性异质性，可逆的内吞作用抑制的临床应用可能会极大地提高 ADCC 介导的治疗性抗体的临床获益。
