Treatment of Human Tumor Xenografts with Monoclonal Antibody 806 in Combination with a Prototypical Epidermal Growth Factor Receptor–Specific Antibody Generates Enhanced Antitumor Activity

• Published in: Clinical cancer research Vol. 11; no. 17; pp. 6390 - 6399
• Main Authors: PERERA, Rushika M, NARITA, Yoshitaka, OLD, Lloyd J, CAVENEE, Webster K, SCOTT, Andrew M, JOHNS, Terrance G, FURNARI, Frank B, GAN, Hui K, MURONE, Carmel, AHLKVIST, Marika, LUWOR, Rodney B, BURGESS, Antony W, STOCKERT, Elisabeth, JUNGBLUTH, Achim A
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.09.2005
• Subjects: Animals; Antibodies, Monoclonal - metabolism; Antibodies, Monoclonal - pharmacology; antibody therapy; Antineoplastic agents; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Cycle Proteins - metabolism; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p27; Drug Synergism; Drug Therapy, Combination; epidermal growth factor receptor; Female; Gene Expression Regulation, Neoplastic; glioma; Glioma - drug therapy; Glioma - genetics; Glioma - pathology; Humans; Ki-67 Antigen - metabolism; Medical sciences; Mice; Mice, Nude; Mutation; Pharmacology. Drug treatments; receptor internalization; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - immunology; Survival Rate; Tumor Cells, Cultured; Tumor Suppressor Proteins - metabolism; Xenograft Model Antitumor Assays; Antineoplastic agent; Human; Growth factor receptor; Treatment; Monoclonal antibody; Malignant tumor; Heterograft; Heterotransplantation; Biological activity; Epidermal growth factor receptor
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-04-2653

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.