Most clinical anti-EGFR antibodies do not neutralize both wtEGFR and EGFRvIII activation in glioma.

Autor:	Greenall SA; Department of Oncology, Monash University and Monash Health, Clayton, Victoria, Australia.; Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.; Brain Cancer Discovery Collaborative, New South Wales, Australia., McKenzie M; School of Life and Environmental Sciences, Deakin University, Geelong, Victoria, Australia.; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.; Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia., Seminova E; CSIRO Manufacturing, Parkville, Victoria, Australia., Dolezal O; CSIRO Manufacturing, Parkville, Victoria, Australia., Pearce L; CSIRO Manufacturing, Parkville, Victoria, Australia., Bentley J; CSIRO Manufacturing, Parkville, Victoria, Australia., Kuchibhotla M; Cancer Centre, Telethon Kids Institute, Nedlands, Western Australia, Australia., Chen SC; Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.; Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia., McDonald KL; Brain Cancer Discovery Collaborative, New South Wales, Australia.; Cure Brain Cancer Biomarkers and Translational Research Group, Prince of Wales Clinical School, University of New South Wales, New South Wales, Australia., Kornblum HI; The Intellectual and Developmental Disabilities Research Center, University of California, Los Angeles, California, USA., Endersby R; Brain Cancer Discovery Collaborative, New South Wales, Australia.; Cancer Centre, Telethon Kids Institute, Nedlands, Western Australia, Australia., Adams TE; CSIRO Manufacturing, Parkville, Victoria, Australia., Johns TG; Brain Cancer Discovery Collaborative, New South Wales, Australia.; Cancer Centre, Telethon Kids Institute, Nedlands, Western Australia, Australia.
Jazyk:	angličtina
Zdroj:	Neuro-oncology [Neuro Oncol] 2019 Aug 05; Vol. 21 (8), pp. 1016-1027.
DOI:	10.1093/neuonc/noz073
Abstrakt:	Background: Although epidermal growth factor receptor (EGFR) and its truncated, autoactive mutant EGFR variant (v)III are bona fide drivers of tumorigenesis in some gliomas, therapeutic antibodies developed to neutralize this axis have not improved patient survival in a limited number of trials. Previous studies using cells transduced to exogenously express EGFRvIII may have compromised mechanistic studies of anti-EGFR therapeutics. Therefore, we re-assessed the activity of clinical EGFR antibodies in patient-derived gliomaspheres that endogenously express EGFRvIII. Methods: The antitumor efficacy of antibodies was assessed using in vitro proliferation assays and intracranial orthografts. Receptor activation status, antibody engagement, oncogenic signaling, and mechanism of action after antibody treatment were analyzed by immunoprecipitation and western blotting. Tracking of antibody receptor complexes was conducted using immunofluorescence. Results: The EGFR domain III-targeting antibodies cetuximab, necitumumab, nimotuzumab, and matuzumab did not neutralize EGFRvIII activation. Chimeric monoclonal antibody 806 (ch806) neutralized EGFRvIII, but not wild-type (wt)EGFR activation. Panitumumab was the only antibody that neutralized both EGFRvIII and wtEGFR, leading to reduction of p-S6 signaling and superior in vitro and in vivo antitumor activity. Mechanistically, panitumumab induced recycling of receptor but not degradation as previously described. Panitumumab, via its unique avidity, stably cross-linked EGFRvIII to prevent its activation, while ch806 induced a marked reduction in the active EGFRvIII disulphide-bonded dimer. Conclusions: We discovered a previously unknown major resistance mechanism in glioma in that most EGFR domain III-targeting antibodies do not neutralize EGFRvIII. The superior in vitro and in vivo antitumor activity of panitumumab supports further clinical testing of this antibody against EGFRvIII-stratified glioma. (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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