Characterization of ABT-806, a Humanized Tumor-Specific Anti-EGFR Monoclonal Antibody.
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.
AbbVie, Cancer Discovery, North Chicago, Illinois. ed.reilly@abbvie.com.
Edward B
EB
Reilly
AbbVie, Cancer Discovery, North Chicago, Illinois.
Andrew C
AC
Phillips
AbbVie, Cancer Discovery, North Chicago, Illinois.
Fritz G
FG
Buchanan
AbbVie Bioresearch Center, Worcester, Massachusetts.
Gillian
G
Kingsbury
AbbVie, Cancer Discovery, North Chicago, Illinois.
Yumin
Y
Zhang
AbbVie, Cancer Discovery, North Chicago, Illinois.
Jonathan A
JA
Meulbroek
AbbVie, Cancer Discovery, North Chicago, Illinois.
Todd B
TB
Cole
AbbVie, Cancer Discovery, North Chicago, Illinois.
Peter J
PJ
DeVries
AbbVie, Cancer Discovery, North Chicago, Illinois.
Hugh D
HD
Falls
AbbVie Bioresearch Center, Worcester, Massachusetts.
Christine
C
Beam
AbbVie Bioresearch Center, Worcester, Massachusetts.
Jinming
J
Gu
AbbVie, Cancer Discovery, North Chicago, Illinois.
Enrico L
EL
Digiammarino
AbbVie, Cancer Discovery, North Chicago, Illinois.
Joann P
JP
Palma
AbbVie, Cancer Discovery, North Chicago, Illinois.
Cherrie K
CK
Donawho
The Jackson Laboratory, Sacramento, California.
Neal C
NC
Goodwin
Ludwig Institute for Cancer Research, Olivia Newton-John Cancer Research Institute, and La Trobe University, Melbourne, Victoria, Australia.
Andrew M
AM
Scott
D000818:Animals; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000008:administration & dosage* / Q000494:pharmacology; D066246:ErbB Receptors / Q000276:immunology* / Q000378:metabolism*; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D059039:Standard of Care; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C518939:monoclonal antibody 806; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab; C000604456:depatuxizumab