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 expressed on most cancers especially carcinomas. 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 Fc-gamma 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, T-cell mediated killing via the granzyme/perforin system, antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and phagocytosis. This results in destruction of tumour cells in the peritoneal cavity, thereby eliminating a major cause of malignant ascites.

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 as 6-hour infusion were investigated in a dedicated study in 13 patients with symptomatic malignant ascites due to EpCAM-positive carcinomas.

Catumaxomab was detectable in 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.

Absorption

Catumaxomab is administered via the intraperitoneal route and therefore is immediately available at the targeted site of malignant cells in the peritoneal cavity.

Distribution

Upon intraperitoneal infusion, catumaxomab distributes in ascites fluid as the site of action. Mean and median C_max for ascites fluid were 7122 and 3270 pg/mL, respectively.

After intraperitoneal administration and binding to target cells in the peritoneal cavity, residual catumaxomab reaches systemic circulation in intact form. The geometric mean plasma C_max was 0.5 ng/ml (range 0 to 2.3), and the geometric mean plasma AUC was 1.7 day* ng/ml (range < LLOQ (lower limit of quantification) to 13.5).

The variability between subjects in ascites and plasma catumaxomab levels was high, due to varying ascites volume and malignant cell burden in the peritoneal cavity.

Metabolism and elimination

The metabolism and elimination of catumaxomab is similar to endogenous IgG i.e. primarily via proteolytic catabolism throughout the body; it does not rely primarily on elimination through the kidneys and liver.

For systemic catumaxomab, i.e. residual (not target-bound) catumaxomab that reached the circulation from the peritoneal cavity, geometric mean apparent terminal plasma elimination half-life (t_1/2) was 2.5 days (range 0.7 to 17.5).

Special populations

No studies have been conducted.

Administration of catumaxomab in animal models did not result in any signs of abnormal or product 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.