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Endocytosis Inhibition in Humans to Improve Responses to ADCC-Mediating Antibodies.
Cell ( IF 45.5 ) Pub Date : 2020-03-05 , DOI: 10.1016/j.cell.2020.02.019
Hui Yi Chew 1 , Priscila O De Lima 1 , Jazmina L Gonzalez Cruz 1 , Blerida Banushi 1 , Godwins Echejoh 1 , Lingbo Hu 1 , Shannon R Joseph 1 , Benedict Lum 1 , James Rae 2 , Jake S O'Donnell 1 , Lilia Merida de Long 1 , Satomi Okano 1 , Brigid King 1 , Rachael Barry 1 , Davide Moi 1 , Roberta Mazzieri 1 , Ranjeny Thomas 1 , Fernando Souza-Fonseca-Guimaraes 1 , Matthew Foote 3 , Adam McCluskey 4 , Phillip J Robinson 5 , Ian H Frazer 1 , Nicholas A Saunders 1 , Robert G Parton 2 , Riccardo Dolcetti 1 , Katharine Cuff 6 , Jennifer H Martin 7 , Benedict Panizza 6 , Euan Walpole 6 , James W Wells 1 , Fiona Simpson 1
Affiliation  

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.



中文翻译:

抑制人类内吞作用,以改善对ADCC介导抗体的反应。

在体内安全和受控地控制胞吞作用可能具有破坏性的治疗潜力。在这里,我们证明了止吐/抗精神病药物氯丙嗪可被重新利用,以可逆性抑制治疗性单克隆抗体靶向的膜蛋白的体内内吞作用,正如我们的人类肿瘤离体直接证明的那样分析。暂时的内吞作用抑制作用可提高靶标的利用率,并提高天然杀伤细胞介导的抗体依赖性细胞毒作用(ADCC)的效率,ADCC是IgG1抗体诱导的临床反应的介体,在此证明了西妥昔单抗,曲妥珠单抗和avelumab的作用。下游信号通路的广泛分析排除了靶点毒性。通过克服经常表征不良反应或抗药性肿瘤的药物靶标可用性的异质性,可逆内吞作用抑制的临床应用可大大改善介导ADCC的治疗性抗体的临床益处。

更新日期:2020-03-05
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