Pharmacokinetics, immunogenicity and bioactivity of the therapeutic antibody catumaxomab intraperitoneally administered to cancer patients

center dot The trifunctional antibody catumaxomab is a highly effective anti-cancer therapeutic that is administered to patients suffering from malignant ascites intraperitoneally (i.p.) in microgram (mu g) doses. So far, no clinical pharmacokinetic data are available. WHAT THIS STUDY ADDS center dot Catumaxomab attains effective local concentrations in the ascites fluid and shows low systemic exposure with an acceptable safety profile confirming the appropriateness of the i.p. application scheme. AIMS Catumaxomab is the first EMEA approved trifunctional anti-EpCAMxanti-CD3 antibody for the treatment of cancer patients with malignant ascites. A phase II pharmacokinetic study was conducted to determine local and systemic antibody concentrations and anti-drug antibody (ADA) development. METHODS Thirteen cancer patients with symptomatic malignant ascites were treated with four ascending doses of 10, 20, 50, and 150 mu g catumaxomab intraperitoneally (i.p.) infused on days 0, 3, 6 or 7 and 10. The pharmacokinetics of catumaxomab were studied by implementation of supportive data from a non clinical mouse tumour model. Additionally, ADA development was monitored. RESULTS Ten out of 13 patients were evaluable for pharmacokinetic analysis. Catumaxomab became increasingly concentrated in ascites during the course of treatment, attaining effective concentrations in the ng ml-1 range. Catumaxomab remained immunologically active even after several days in the circulation. The observed systemic catumaxomab exposure was low (< 1%), with a maximal median plasma concentration (C-max) of 403 pg ml-1. The mean elimination half-life in the plasma was 2.13 days. All patients developed ADA, but not before the last infusion. High observed inter-individual variability and low systemic exposure may be explained by the inverse correlation between tumour burden, effector cell numbers and systemic antibody bioavailability as demonstrated in a defined mouse tumour model. CONCLUSIONS Based on the high and effective local concentrations, low systemic exposure and acceptable safety profile, we confirmed that the i.p. application scheme of catumaxomab for the treatment of malignant ascites is appropriate.