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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antibody-Dependent Cell Cytotoxicity / drug effects*
  • Antibody-Dependent Cell Cytotoxicity / immunology
  • Antigen Presentation / drug effects
  • Biopsy
  • Cetuximab / pharmacology
  • Drug Delivery Systems / methods
  • Drug Resistance, Neoplasm / genetics
  • Drug Resistance, Neoplasm / immunology*
  • Endocytosis / drug effects
  • Endocytosis / immunology
  • Heterografts
  • Humans
  • Immunoglobulin G / genetics
  • Immunoglobulin G / immunology
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology
  • MCF-7 Cells
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Mice
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / immunology
  • Prochlorperazine / pharmacology*
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Trastuzumab / pharmacology

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Immunoglobulin G
  • Membrane Proteins
  • avelumab
  • Trastuzumab
  • Cetuximab
  • Prochlorperazine