Chew et al. detailed a strategy for improving therapeutic IgG1 mAb efficacy through temporarily inhibiting endocytosis, resulting in more efficient NK cell-mediated ADCC via receptor clustering and greater cell surface retention of target antigen. Using a dynamin inhibitor (Dyngo-4a) or the approved endocytosis inhibitor prochlorperazine (PCZ) in combination with multiple therapeutic mAbs, including anti-PD-L1, blocking endocytosis in several tumor models resulted in increased surface target antigen levels and improved efficacy. In a pilot clinical trial, a single I.V. dose of PCZ significantly increased cetuximab-binding sites, supporting the potential for enhanced efficacy.
Contributed by Katherine Turner
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.
Author Info: (1) The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba QLD 4102, Australia. (2) The University of Queensland Diamantina Institute, Universit
Author Info: (1) The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba QLD 4102, Australia. (2) The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba QLD 4102, Australia. (3) The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba QLD 4102, Australia. (4) The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba QLD 4102, Australia. (5) The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba QLD 4102, Australia. (6) The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba QLD 4102, Australia. (7) The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba QLD 4102, Australia. (8) The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba QLD 4102, Australia. (9) Cell Biology and Molecular Medicine Division, Institute for Molecular Bioscience, University of Queensland, St Lucia QLD 4072, Australia; Australia Centre for Microscopy and Microanalysis, University of Queensland, St Lucia QLD 4072, Australia. (10) The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba QLD 4102, Australia. (11) The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba QLD 4102, Australia. (12) The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba QLD 4102, Australia. (13) The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba QLD 4102, Australia. (14) The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba QLD 4102, Australia. (15) The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba QLD 4102, Australia. (16) The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba QLD 4102, Australia. (17) The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba QLD 4102, Australia. (18) The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba QLD 4102, Australia. (19) Princess Alexandra Hospital, Brisbane QLD 4102, Australia. (20) Centre for Chemistry, Biology and Clinical Pharmacology, The University of Newcastle, Callaghan NSW 2308, Australia. (21) Cell Signaling Unit, Children's Medical Research Institute, The University of Sydney, Sydney NSW 2145, Australia. (22) The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba QLD 4102, Australia. (23) The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba QLD 4102, Australia. (24) Cell Biology and Molecular Medicine Division, Institute for Molecular Bioscience, University of Queensland, St Lucia QLD 4072, Australia; Australia Centre for Microscopy and Microanalysis, University of Queensland, St Lucia QLD 4072, Australia. (25) The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba QLD 4102, Australia. (26) Princess Alexandra Hospital, Brisbane QLD 4102, Australia; Faculty of Medicine, University of Queensland, Woolloongabba QLD 4102, Australia. (27) Princess Alexandra Hospital, Brisbane QLD 4102, Australia; Centre for Chemistry, Biology and Clinical Pharmacology, The University of Newcastle, Callaghan NSW 2308, Australia. (28) Princess Alexandra Hospital, Brisbane QLD 4102, Australia; Faculty of Medicine, University of Queensland, Woolloongabba QLD 4102, Australia. (29) Princess Alexandra Hospital, Brisbane QLD 4102, Australia; Faculty of Medicine, University of Queensland, Woolloongabba QLD 4102, Australia. (30) The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba QLD 4102, Australia. (31) The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba QLD 4102, Australia. Electronic address: f.simpson@uq.edu.au.
