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. 2020 Mar 5;180(5):895-914.e27.
doi: 10.1016/j.cell.2020.02.019.

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

Hui Yi Chew  1 , Priscila O De Lima  1 , Jazmina L Gonzalez Cruz  1 , Blerida Banushi  1 , Godwins Echejoh  1 , Lingbo Hu  1 , Shannon R Joseph  1 , Benedict Lum  1 , James Rae  2 , Jake S O'Donnell  1 , Lilia Merida de Long  1 , Satomi Okano  1 , Brigid King  1 , Rachael Barry  1 , Davide Moi  1 , Roberta Mazzieri  1 , Ranjeny Thomas  1 , Fernando Souza-Fonseca-Guimaraes  1 , Matthew Foote  3 , Adam McCluskey  4 , Phillip J Robinson  5 , Ian H Frazer  1 , Nicholas A Saunders  1 , Robert G Parton  2 , Riccardo Dolcetti  1 , Katharine Cuff  6 , Jennifer H Martin  7 , Benedict Panizza  6 , Euan Walpole  6 , James W Wells  1 , Fiona Simpson  8
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Endocytosis Inhibition in Humans to Improve Responses to ADCC-Mediating Antibodies

Hui Yi Chew et al. Cell. .

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.

Keywords: antibody-dependent cellular cytotoxicity; avelumab; cetuximab; endocytosis; epidermal growth factor receptor; monoclonal antibody therapy; natural killer cell; prochlorperazine; programmed death ligand 1; trastuzumab.

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Conflict of interest statement

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.

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