Journal article

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

Hui Yi Chew, Priscila O De Lima, Jazmina L Gonzalez Cruz, Blerida Banushi, Godwins Echejoh, Lingbo Hu, Shannon R Joseph, Benedict Lum, James Rae, Jake S O'Donnell, Lilia Merida de Long, Satomi Okano, Brigid King, Rachael Barry, Davide Moi, Roberta Mazzieri, Ranjeny Thomas, Fernando Souza-Fonseca-Guimaraes, Matthew Foote, Adam McCluskey Show all

Cell | CELL PRESS | Published : 2020

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 si..

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Grants

Awarded by NHMRC Career Development Award


Awarded by Cancer Council Queensland


Awarded by National Breast Cancer Foundation


Funding Acknowledgements

We thank the participants, families, and support staff who contributed to the pilot clinical study. The authors acknowledge the Translational Research Institute for providing the excellent research environment and core facilities that enabled this research: Microscopy, Flow Cytometry, Histology and Biological Resource Core Facilities. This work was supported by University of Queensland (UQ) IPRS scholarship (G.E.), UQ International scholarships (L.H., P.O.D.L., and H.Y.C.), NHMRC Career Development Award (456155), Cancer Council Queensland (1041390), the National Breast Cancer Foundation IN-15003, Queensland Head and Neck Cancer Centre and International Rotary Club (Nundah) to F.S., and the Princess Alexandra Research Foundation (B.B., S.R.J., and F.S.).