Human epidermal growth factor receptor 2 (HER2/neu) is an important target for the treatment of the breast
cancers in which it is overexpressed. However, no approved anti-HER2/neu
therapy is available for the majority of
breast cancer patients, who express HER2/neu at low levels (with scores of 1+ or 2+/fluorescence in situ hybridization-negative). The trifunctional antibody
ertumaxomab targets HER2/neu, CD3, and activating Fcgamma receptors. In presence of
ertumaxomab, tri-cell complexes consisting of
tumor cells, T cells, and accessory cells form to cause
tumor cell lysis. In a phase I trial with metastatic
breast cancer patients,
ertumaxomab could be applied safely and resulted in radiographically confirmed clinical responses. In this study, we compare
ertumaxomab- and
trastuzumab-mediated killing of
cancer cell lines that express HER2/neu at low and high levels. Under optimal conditions for
trastuzumab-mediated destruction of HER2/neu-overexpressing cells, only
ertumaxomab was able to mediate the elimination of tumor cell lines that express HER2/neu at low levels (1+).
Ertumaxomab-mediated activity was accompanied by a Th1-based
cytokine release, a unique mode of action of trifunctional
antibodies. Competitive binding studies with
trastuzumab and 520C9 mapped the binding site of
ertumaxomab to the extracellular regions II and III of the HER2/neu ectodomain. This site is distinct from the binding site of
trastuzumab, so that HER2/neu-expressing
tumor cells can be eliminated by
ertumaxomab in the presence of high amounts of
trastuzumab. The ability of
ertumaxomab to induce cytotoxicity against various tumor cell lines, including those with low HER2/neu
antigen density, may provide a novel therapeutic option for
breast cancer patients who are not eligible for
trastuzumab treatment.