title: Therapeutic anti-EGFR antibody 806 generates responses in murine de novo EGFR mutant-dependent lung carcinomas.
abstract: Activating EGFR mutations occur in human non-small cell lung cancer (NSCLC), with 5% of human lung squamous cell carcinomas having EGFRvIII mutations and approximately 10%-30% of lung adenocarcinomas having EGFR kinase domain mutations. An EGFR-targeting monoclonal antibody, mAb806, recognizes a conformational epitope of WT EGFR as well as the truncated EGFRvIII mutant. To explore the anticancer spectrum of this antibody for EGFR targeted cancer therapy, mAb806 was used to treat genetically engineered mice with lung tumors that were driven by either EGFRvIII or EGFR kinase domain mutations. Our results demonstrate that mAb806 is remarkably effective in blocking EGFRvIII signaling and inducing tumor cell apoptosis, resulting in dramatic tumor regression in the EGFRvIII-driven murine lung cancers. Another EGFR-targeting antibody, cetuximab, failed to show activity in these lung tumors. Furthermore, treatment of murine lung tumors driven by the EGFR kinase domain mutation with mAb806 also induced significant tumor regression, albeit to a less degree than that observed in EGFRvIII-driven tumors. Taken together, these data support the hypothesis that mAb806 may lead to significant advancements in the treatment of the population of NSCLC patients with these 2 classes of EGFR mutations.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Danan
authors.initials: D
authors.lastname: Li
authors.forename: Hongbin
authors.initials: H
authors.lastname: Ji
authors.forename: Sara
authors.initials: S
authors.lastname: Zaghlul
authors.forename: Kate
authors.initials: K
authors.lastname: McNamara
authors.forename: Mei-Chih
authors.initials: MC
authors.lastname: Liang
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimamura
authors.forename: Shigeto
authors.initials: S
authors.lastname: Kubo
authors.forename: Masaya
authors.initials: M
authors.lastname: Takahashi
authors.forename: Lucian R
authors.initials: LR
authors.lastname: Chirieac
authors.forename: Robert F
authors.initials: RF
authors.lastname: Padera
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
authors.forename: Achim A
authors.initials: AA
authors.lastname: Jungbluth
authors.forename: Webster K
authors.initials: WK
authors.lastname: Cavenee
authors.forename: Lloyd J
authors.initials: LJ
authors.lastname: Old
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis; D000068818:Cetuximab; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009154:Mutation; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D010766:Phosphorylation
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019941:Cyclin-Dependent Kinase Inhibitor p16; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors; D000068818:Cetuximab