Catumaxomab

Catumaxomab is a trifunctional rat-mouse hybrid monoclonal antibody that is specifically directed against the epithelial cell adhesion molecule (EpCAM) and the CD3 antigen. The EpCAM antigen is overexpressed on most carcinomas (Table 2). CD3 is expressed on mature T-cells as a component of the T-cell receptor. A third functional binding site in the Fc-region of catumaxomab enables interaction with accessory immune cells via Fcγ receptors. Due to catumaxomab’s binding properties, tumour cells, T-cells and accessory immune cells come in close proximity. Thereby, a concerted immunoreaction against tumour cells is induced which includes different mechanisms of action such as T-cell activation, antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and phagocytosis. This results in destruction of tumour cells.

Table 2. EpCAM expression in most relevant ascites causing cancer types:

^* = lobular breast cancer

Pharmacodynamic effects

The anti-tumour activity of catumaxomab has been demonstrated in vitro and in vivo. Effective catumaxomab-mediated killing of tumour cells in vitro was observed for target cells with low and high expression of the EpCAM antigen, independent of the primary tumour type. The in vivo anti-tumour activity of catumaxomab was confirmed in an immunologically compromised mouse model of ovarian carcinoma, where tumour development was delayed by an intraperitoneal treatment with catumaxomab and human peripheral blood mononuclear cells.

Pharmacokinetics of catumaxomab during and after four intraperitoneal infusions of 10, 20, 50 and 150 micrograms catumaxomab were investigated in 13 patients with symptomatic malignant ascites due to EpCAM-positive carcinomas.

The variability between subjects was high. The geometric mean plasma C_max was approximately 0.5 ng/ml (range 0 to 2.3), and the geometric mean plasma AUC was approximately 1.7 day* ng/ml (range < LLOQ (lower limit of quantification) to 13.5). The geometric mean apparent terminal plasma elimination half-life (t_1/2) was approximately 2.5 days (range 0.7 to 17).

Catumaxomab was detectable in the ascites fluid and in plasma. The concentrations increased with the number of infusions and the doses applied in most patients. Plasma levels tended to decline after achieving a maximum after each dose.

Special populations

No studies have been conducted.

Administration of catumaxomab in animal models did not result in any signs of abnormal or drug-related acute toxicity or signs of local intolerance at the injection/infusion site. However, these findings are of limited value due to the high species-specificity of catumaxomab.

Repeated-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity studies have not been performed.