Cancer Res. 2009 May 15;69(10):4270-6. Epub 2009 May 12.
The trifunctional antibody ertumaxomab destroys tumor cells that express low levels of human epidermal growth factor receptor 2.
Jäger M,
Schoberth A,
Ruf P,
Hess J,
Lindhofer H.
TRION Research GmbH, Martinsried, Germany.
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.
PMID: 19435924 [PubMed - indexed for MEDLINE]
Expert Opin Investig Drugs. 2008 Oct;17(10):1553-8.
Ertumaxomab: a trifunctional antibody for breast cancer treatment.
Kiewe P,
Thiel E.
Charité Campus Benjamin Franklin, Department of Hematology and Oncology, Hindenburgdamm 30/31, D-12200 Berlin, Germany.
philipp.kiewe@charite.de
Ertumaxomab is an intact bispecific antibody targeting HER2/neu and CD3 with preferential binding to activating Fcgamma type I/III-receptors, resulting in the formation of a tri-cell complex among tumour cell, T cell and accessory cell. Recently, the antibody demonstrated antitumour efficacy against HER2/neu low-expressing tumours resistant to trastuzumab. Data from a completed Phase I study in metastatic breast cancer patients indicates strong immune responses. Owing to efficient tumour cell destruction by humoral and T-cell-dependent mechanisms, differing from conventional HER2/neu directed treatments, and a potential for long-lasting antitumour immunoreactivity, ertumaxomab is at present investigated within Phase II studies enrolling metastatic breast cancer patients even without HER2/neu gene amplification.
PMID: 18808314 [PubMed - indexed for MEDLINE]
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