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Title: Characterization of ABT-806, a Humanized Tumor-Specific Anti-EGFR Monoclonal Antibody.
Authors: Reilly, Edward B;Phillips, Andrew C;Buchanan, Fritz G;Kingsbury, Gillian;Zhang, Yumin;Meulbroek, Jonathan A;Cole, Todd B;DeVries, Peter J;Falls, Hugh D;Beam, Christine;Gu, Jinming;Digiammarino, Enrico L;Palma, Joann P;Donawho, Cherrie K;Goodwin, Neal C;Scott, Andrew M
Affiliation: Ludwig Institute for Cancer Research, Olivia Newton-John Cancer Research Institute, and La Trobe University, Melbourne, Victoria, Australia
AbbVie, Cancer Discovery, North Chicago, Illinois.
AbbVie, Cancer Discovery, North Chicago, Illinois.
AbbVie Bioresearch Center, Worcester, Massachusetts.
The Jackson Laboratory, Sacramento, California.
Issue Date: 2-Mar-2015
Citation: Molecular Cancer Therapeutics 2015; 14(5): 1141-51
Abstract: Despite clinical efficacy, current approved agents targeting EGFR are associated with on-target toxicities as a consequence of disrupting normal EGFR function. MAb 806 is a novel EGFR antibody that selectively targets a tumor-selective epitope suggesting that a mAb 806-based therapeutic would retain antitumor activity without the on-target toxicities associated with EGFR inhibition. To enable clinical development, a humanized variant of mAb 806 designated ABT-806 was generated and is currently in phase 1 trials. We describe the characterization of binding and functional properties of ABT-806 compared with the clinically validated anti-EGFR antibody cetuximab. ABT-806 binds the mutant EGFRvIII with high affinity and, relative to cetuximab, exhibits increased potency against glioblastoma multiforme cell line and patient-derived xenografts expressing this form of the receptor. ABT-806 also inhibits the growth of squamous cell carcinoma xenograft models expressing high levels of wild-type EGFR, associated with inhibition of EGFR signaling, although higher doses of ABT-806 than cetuximab are required for similar activity. ABT-806 enhances in vivo potency of standard-of-care therapies used to treat glioblastoma multiforme and head and neck squamous cell carcinoma. An indium-labeled version of ABT-806, [(111)In]-ABT-806, used to investigate the relationship between dose and receptor occupancy, revealed greater receptor occupancy at lowers doses in an EGFRvIII-expressing model and significant uptake in an orthotopic model. Collectively, these results suggest that ABT-806 may have antitumor activity superior to cetuximab in EGFRvIII-expressing tumors, and similar activity to cetuximab in tumors highly overexpressing wild-type EGFR with reduced toxicity. Mol Cancer Ther; 14(5); 1141-51. ©2015 AACR.
Internal ID Number: 25731184
DOI: 10.1158/1535-7163.MCT-14-0820
Type: Journal Article
Appears in Collections:Journal articles

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