| Literature DB >> 32142680 |
Hui Yi Chew1, Priscila O De Lima1, Jazmina L Gonzalez Cruz1, Blerida Banushi1, Godwins Echejoh1, Lingbo Hu1, Shannon R Joseph1, Benedict Lum1, James Rae2, Jake S O'Donnell1, Lilia Merida de Long1, Satomi Okano1, Brigid King1, Rachael Barry1, Davide Moi1, Roberta Mazzieri1, Ranjeny Thomas1, Fernando Souza-Fonseca-Guimaraes1, Matthew Foote3, Adam McCluskey4, Phillip J Robinson5, Ian H Frazer1, Nicholas A Saunders1, Robert G Parton2, Riccardo Dolcetti1, Katharine Cuff6, Jennifer H Martin7, Benedict Panizza6, Euan Walpole6, James W Wells1, Fiona Simpson8.
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.Entities:
Keywords: antibody-dependent cellular cytotoxicity; avelumab; cetuximab; endocytosis; epidermal growth factor receptor; monoclonal antibody therapy; natural killer cell; prochlorperazine; programmed death ligand 1; trastuzumab
Year: 2020 PMID： 32142680 DOI： 10.1016/j.cell.2020.02.019
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582