1. Academic Validation
  2. Characterization of ABT-806, a Humanized Tumor-Specific Anti-EGFR Monoclonal Antibody

Characterization of ABT-806, a Humanized Tumor-Specific Anti-EGFR Monoclonal Antibody

  • Mol Cancer Ther. 2015 May;14(5):1141-51. doi: 10.1158/1535-7163.MCT-14-0820.
Edward B Reilly 1 Andrew C Phillips 2 Fritz G Buchanan 2 Gillian Kingsbury 3 Yumin Zhang 2 Jonathan A Meulbroek 2 Todd B Cole 2 Peter J DeVries 2 Hugh D Falls 2 Christine Beam 3 Jinming Gu 3 Enrico L Digiammarino 2 Joann P Palma 2 Cherrie K Donawho 2 Neal C Goodwin 4 Andrew M Scott 5
Affiliations

Affiliations

  • 1 AbbVie, Cancer Discovery, North Chicago, Illinois. ed.reilly@abbvie.com.
  • 2 AbbVie, Cancer Discovery, North Chicago, Illinois.
  • 3 AbbVie Bioresearch Center, Worcester, Massachusetts.
  • 4 The Jackson Laboratory, Sacramento, California.
  • 5 Ludwig Institute for Cancer Research, Olivia Newton-John Cancer Research Institute, and La Trobe University, Melbourne, Victoria, Australia.
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.

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