title: Treatment of human tumor xenografts with monoclonal antibody 806 in combination with a prototypical epidermal growth factor receptor-specific antibody generates enhanced antitumor activity.
abstract: Monoclonal antibody (mAb) 806 is a novel epidermal growth factor receptor (EGFR) antibody with significant antitumor activity that recognizes a mutant EGFR commonly expressed in glioma known as delta2-7 EGFR (de2-7 EGFR or EGFRvIII) and a subset of the wild-type (wt) EGFR found in cells that overexpress the receptor. We have used two human xenograft mouse models to examine the efficacy of mAb 806 in combination with mAb 528, a prototypical anti-EGFR antibody with similar specificity to cetuximab. Treatment of nude mice, bearing s.c. or i.c. tumor human xenografts expressing the wt or de2-7 EGFR, with mAbs 806 and 528 in combination resulted in additive and in some cases synergistic, antitumor activity. Interestingly, mAb 528 was also effective against xenografts expressing the ligand independent de2-7 EGFR when used as a single agent, showing that its antitumor activity is not merely mediated through inhibition of ligand binding. When used as single agents, neither mAbs 806 or 528 induced down-regulation of the de2-7 EGFR either in vitro or in vivo. In contrast, the combination of antibodies produced a rapid and dramatic decrease in the total cell surface de2-7 EGFR both in vitro and in xenografts. Consistent with this decrease in total cell surface de2-7 EGFR, we observed up-regulation of the cell cycle inhibitor p27(KIP1) and a decrease in tumor cell proliferation as measured by Ki-67 immunostaining when the antibodies were used in combination in vivo. Thus, mAb 806 can synergize with other EGFR-specific antibodies thereby providing a rationale for its translation into the clinic.
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne Branch, Tumor Targeting Program, Austin Hospital, Heidelberg, Victoria, Australia.
authors.forename: Rushika M
authors.initials: RM
authors.lastname: Perera
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Narita
authors.forename: Frank B
authors.initials: FB
authors.lastname: Furnari
authors.forename: Hui K
authors.initials: HK
authors.lastname: Gan
authors.forename: Carmel
authors.initials: C
authors.lastname: Murone
authors.forename: Marika
authors.initials: M
authors.lastname: Ahlkvist
authors.forename: Rodney B
authors.initials: RB
authors.lastname: Luwor
authors.forename: Antony W
authors.initials: AW
authors.lastname: Burgess
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Stockert
authors.forename: Achim A
authors.initials: AA
authors.lastname: Jungbluth
authors.forename: Lloyd J
authors.initials: LJ
authors.lastname: Old
authors.forename: Webster K
authors.initials: WK
authors.lastname: Cavenee
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
authors.forename: Terrance G
authors.initials: TG
authors.lastname: Johns
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D066246:ErbB Receptors / Q000235:genetics* / Q000276:immunology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D019394:Ki-67 Antigen; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D066246:ErbB Receptors