Endocytosis Inhibition in Humans to Improve Responses to ADCC-Mediating Antibodies

• Published in: Cell Vol. 180; no. 5; pp. 895 - 914.e27
• Main Authors: Chew, Hui Yi, De Lima, Priscila O., Gonzalez Cruz, Jazmina L., Banushi, Blerida, Echejoh, Godwins, Hu, Lingbo, Joseph, Shannon R., Lum, Benedict, Rae, James, O’Donnell, Jake S., Merida de Long, Lilia, Okano, Satomi, King, Brigid, Barry, Rachael, Moi, Davide, Mazzieri, Roberta, Thomas, Ranjeny, Souza-Fonseca-Guimaraes, Fernando, Foote, Matthew, McCluskey, Adam, Robinson, Phillip J., Frazer, Ian H., Saunders, Nicholas A., Parton, Robert G., Dolcetti, Riccardo, Cuff, Katharine, Martin, Jennifer H., Panizza, Benedict, Walpole, Euan, Wells, James W., Simpson, Fiona
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.03.2020
• Subjects: antibody-dependent cellular cytotoxicity; avelumab; cetuximab; endocytosis; epidermal growth factor receptor; monoclonal antibody therapy; natural killer cell; prochlorperazine; programmed death ligand 1; trastuzumab; trastuzumab; prochlorperazine; antibody-dependent cellular cytotoxicity; avelumab; epidermal growth factor receptor; endocytosis; cetuximab; programmed death ligand 1; monoclonal antibody therapy; natural killer cell
• ISSN: 0092-8674; 1097-4172
• 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. [Display omitted] •A strategy for improving the ADCC potential of therapeutic antibodies is presented•Temporary inhibition of endocytosis increases tumor cell antigen presentation•Prochlorperazine could be repurposed to enhance the efficacy of anti-tumor mAbs•Potential to reduce heterogeneity in tumor cell responses to many IgG1 antibodies Endocytosis inhibitors, such as prochlorperazine, can be used to move tumor cell antigens that are the targets of therapeutic monoclonal antibodies but hiding inside the cell to the cell surface for improved therapeutic antibody binding and tumor cell destruction by NK cells.