Endocytosis Inhibition in Humans to Improve Responses to ADCC-Mediating Antibodies.
Animals
Antibodies, Monoclonal
/ pharmacology
Antibodies, Monoclonal, Humanized
/ pharmacology
Antibody-Dependent Cell Cytotoxicity
/ drug effects
Antigen Presentation
/ drug effects
Biopsy
Cetuximab
/ pharmacology
Drug Delivery Systems
/ methods
Drug Resistance, Neoplasm
/ genetics
Endocytosis
/ drug effects
Heterografts
Humans
Immunoglobulin G
/ genetics
Killer Cells, Natural
/ drug effects
MCF-7 Cells
Membrane Proteins
/ genetics
Mice
Neoplasms
/ drug therapy
Prochlorperazine
/ pharmacology
Signal Transduction
/ drug effects
Trastuzumab
/ pharmacology
antibody-dependent cellular cytotoxicity
avelumab
cetuximab
endocytosis
epidermal growth factor receptor
monoclonal antibody therapy
natural killer cell
prochlorperazine
programmed death ligand 1
trastuzumab
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
05 03 2020
05 03 2020
Historique:
received:
03
09
2019
revised:
19
01
2020
accepted:
07
02
2020
entrez:
7
3
2020
pubmed:
7
3
2020
medline:
18
8
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32142680
pii: S0092-8674(20)30163-X
doi: 10.1016/j.cell.2020.02.019
pii:
doi:
Substances chimiques
Antibodies, Monoclonal
0
Antibodies, Monoclonal, Humanized
0
Immunoglobulin G
0
Membrane Proteins
0
avelumab
KXG2PJ551I
Trastuzumab
P188ANX8CK
Cetuximab
PQX0D8J21J
Prochlorperazine
YHP6YLT61T
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
895-914.e27Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests other than the following: The avelumab work was conducted under investigator-initiated contract with Merck KGaA. The costs of the experiments were paid for by Merck KGaA and avelumab supplied by Merck. This work utilizes technology subject to the following patents: 2015 WO2014063206-A1 “classifying epidermal growth factor receptor positive tumor into subtype eg epidermal growth factor receptor antagonist sensitive subtype, involves analyzing ligand-induced epidermal growth factor receptor internalization status of tumor.” Simpson, F., Saunders, N.A.; 2015 WO2014063205-A1 “composition useful in kit for treating tumor, preferably cell surface antigen positive tumor eg cancerous tumors, comprises antibody that binds to cell surface antigen of tumor and inhibitor of receptor mediated endocytosis” Simpson, F., Saunders, N.A.