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.

Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity

“…At least three independent groups, (Johns et al, 2003;Huang et al, 2004;Matar et al, 2004;Perera et al, 2005). In further support of this approach we have observed promising clinical activity of the combination of an EGFR TKI and cetuximab, a monoclonal antibody directed at the extracellular domain of the EGFR .…”

Targeting the HER family with Pan-HER effectively overcomes resistance to cetuximab

“…Sym004 led to rapid internalization and degradation of EGFR in cetuximab-resistant H226 clones with subsequent loss of proliferative effects (20). In line with these data, Pedersen et al reported that Sym004 synergistically inhibited skin, lung and HNSCC cell growth through efficient target internalization and degradation (34 528) showed synergistic anti-tumor activity in glioma and squamous cell cancer xenograft models (37).…”

A phase I clinical trial with monoclonal antibody ch806 targeting transitional state and mutant epidermal growth factor receptors

“…Intracranial xenografts expressing the de2-7 EGFR have also been shown to be inhibited by mAb 806, and this observation represents the only reported mAb that has such effects on gliomas in vivo (30). In conjunction with other EGFR inhibitors such as the mAb 528, or the tyrosine kinase inhibitor AG1478, mAb 806 shows synergistic effects on xenograft growth, with Ͼ60% of established tumours showing complete regressions (29,31).…”