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Endocytosis Inhibition in Humans to Improve Responses to ADCC-Mediating Antibodies
Cell ( IF 36.216 ) Pub Date : 2020-03-05 , DOI: 10.1016/j.cell.2020.02.019
Hui Yi Chew; Priscila O. De Lima; Jazmina L. Gonzalez Cruz; Blerida Banushi; Godwins Echejoh; Lingbo Hu; Shannon R. Joseph; Benedict Lum; James Rae; Jake S. O’Donnell; Lilia Merida de Long; Satomi Okano; Brigid King; Rachael Barry; Davide Moi; Roberta Mazzieri; Ranjeny Thomas; Fernando Souza-Fonseca-Guimaraes; Fiona Simpson

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.
更新日期:2020-03-05

 

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