1. ¹Department of Medicine III, Division of Hematology/Oncology, University of Erlangen-Nürnberg, Krankenhausstrae 12, Erlangen 91054, Germany
2. ²Department of Internal Medicine and Oncology. University Medical Center Utrecht, The Netherlands
3. ³Immunotherapy Laboratory, Department of Immunology, University Medical Center Utrecht, The Netherlands
4. ⁴Department of Gynecology, University of Erlangen-Nürnberg, Germany
5. ⁵Department of Nuclear Medicine, University of Goettingen, Germany
6. ⁶Department of Pathology, Hospital Friedrichshafen, Germany
7. ⁷Medarex Inc., Annandale, New Jersey
8. ⁸Genmab, Utrecht, The Netherlands
9. ⁹Department of Nuclear Medicine, University of Heidelberg, Germany

Correspondence: Dr R Repp, E-mail: Roland.Repp@med3.imed.uni-erlangen.de

¹⁰These authors contributed equally to this study

^†Dr Wolfgang Becker sadly passed away recently.

Received 10 February 2003; Revised 18 August 2003; Accepted 9 September 2003.

Abstract

A phase I study of the bispecific antibody MDX-H210 in combination with granulocyte colony-stimulating factor (G-CSF) was performed in stage IV breast carcinoma patients, overexpressing HER-2/neu. MDX-H210, constructed by crosslinking antigen binding fragments (F(ab') fragments) of monoclonal antibody (mAb) H22 to Fc gamma receptor I (FcRI), and mAb 520C9 to HER-2/neu, respectively, mediates the lysis of tumour cells in vitro, and in human FcRI transgenic mouse models. The proto-oncogene HER-2/neu is overexpressed in approximately 30% of breast cancer patients, and represents a promising target for antibody-based immunotherapy. Fc gamma receptor I (CD64) is an effective trigger molecule, which is expressed on monocytes/macrophages, immature dendritic cells, and G-CSF-primed polymorphonuclear cells (PMN). Patients received G-CSF (Filgrastim) for 8 consecutive days, and cohorts of three patients were treated on day 4 with escalating, single doses of MDX-H210. A total of 30 patients were included, and treatment was generally well tolerated, without reaching dose-limiting toxicity. Side effects consisted mainly of fever and short periods of chills, which were timely related to elevated plasma levels of interleukin 6 and tumour necrosis factor alpha. In the last two cohorts, MDX-H210 plasma levels exceeded 1 g ml^-1, and on circulating myeloid cells >50% saturation of FcRI was found until day 4. These effector cells were highly effective in antibody-dependent cell-mediated cytotoxicity. Immunohistochemical analyses of tumour biopsies in individual patients documented infiltration of monocytes and PMN after MDX-H210 infusion. Although the clinical course of the disease was not altered by the single dose of MDX-H210, a favourable toxicity profile – even at high doses – and remarkable biological effects were seen when combined with G-CSF. Therefore, the combination of G-CSF and MDX-H210 should be evaluated in further immunotherapeutical strategies.