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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.
Austin Authors: Perera, Rushika M;Narita, Yoshitaka;Furnari, Frank B;Gan, Hui K ;Murone, Carmel ;Ahlkvist, Marika;Luwor, Rodney B;Burgess, Antony W;Stockert, Elisabeth;Jungbluth, Achim A;Old, Lloyd J;Cavenee, Webster K;Scott, Andrew M ;Johns, Terrance G
Affiliation: Ludwig Institute for Cancer Research, Melbourne Branch, Tumor Targeting Program, Austin Hospital, Heidelberg, Victoria, Australia
Issue Date: 1-Sep-2005
Publication information: Clinical Cancer Research; 11(17): 6390-9
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.
Gov't Doc #: 16144944
DOI: 10.1158/1078-0432.CCR-04-2653
Type: Journal Article
Subjects: Animals
Antibodies, Monoclonal.metabolism.pharmacology
Antineoplastic Agents.pharmacology
Cell Cycle Proteins.metabolism
Cell Proliferation
Cyclin-Dependent Kinase Inhibitor p27
Drug Synergism
Drug Therapy, Combination
Gene Expression Regulation, Neoplastic
Glioma.drug therapy.genetics.pathology
Ki-67 Antigen.metabolism
Mice, Nude
Receptor, Epidermal Growth Factor.genetics.immunology
Survival Rate
Tumor Cells, Cultured
Tumor Suppressor Proteins.metabolism
Xenograft Model Antitumor Assays
Appears in Collections:Journal articles

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