TY - JOUR
T1 - Endocytosis Inhibition in Humans to Improve Responses to ADCC-Mediating Antibodies
AU - Chew, Hui Yi
AU - De Lima, Priscila O
AU - Gonzalez Cruz, Jazmina L
AU - Banushi, Blerida
AU - Echejoh, Godwins
AU - Hu, Lingbo
AU - Joseph, Shannon R
AU - Lum, Benedict
AU - Rae, James
AU - O'Donnell, Jake S
AU - Merida de Long, Lilia
AU - Okano, Satomi
AU - King, Brigid
AU - Barry, Rachael
AU - Moi, Davide
AU - Mazzieri, Roberta
AU - Thomas, Ranjeny
AU - Souza-Fonseca-Guimaraes, Fernando
AU - Foote, Matthew
AU - McCluskey, Adam
AU - Robinson, Phillip J
AU - Frazer, Ian H
AU - Saunders, Nicholas A
AU - Parton, Robert G
AU - Dolcetti, Riccardo
AU - Cuff, Katharine
AU - Martin, Jennifer H
AU - Panizza, Benedict
AU - Walpole, Euan
AU - Wells, James W
AU - Simpson, Fiona
N1 - Copyright © 2020 Elsevier Inc. All rights reserved.
PY - 2020/3/5
Y1 - 2020/3/5
N2 - 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.
AB - 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.
KW - Animals
KW - Antibodies, Monoclonal/pharmacology
KW - Antibodies, Monoclonal, Humanized/pharmacology
KW - Antibody-Dependent Cell Cytotoxicity/drug effects
KW - Antigen Presentation/drug effects
KW - Biopsy
KW - Cetuximab/pharmacology
KW - Drug Delivery Systems/methods
KW - Drug Resistance, Neoplasm/genetics
KW - Endocytosis/drug effects
KW - Heterografts
KW - Humans
KW - Immunoglobulin G/genetics
KW - Killer Cells, Natural/drug effects
KW - MCF-7 Cells
KW - Membrane Proteins/genetics
KW - Mice
KW - Neoplasms/drug therapy
KW - Prochlorperazine/pharmacology
KW - Signal Transduction/drug effects
KW - Trastuzumab/pharmacology
UR - https://www.scopus.com/pages/publications/85080110879
U2 - 10.1016/j.cell.2020.02.019
DO - 10.1016/j.cell.2020.02.019
M3 - Article
C2 - 32142680
SN - 0092-8674
VL - 180
SP - 895-914.e27
JO - Cell
JF - Cell
IS - 5
ER -
