Endocytosis Inhibition in Humans to Improve Responses to ADCC-Mediating Antibodies.
Cell
; 180(5): 895-914.e27, 2020 03 05.
Article
em En
| MEDLINE
| ID: mdl-32142680
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proclorperazina
/
Resistencia a Medicamentos Antineoplásicos
/
Citotoxicidade Celular Dependente de Anticorpos
/
Neoplasias
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article