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

Abstract

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 microg 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.

Keywords: catumaxomab; immunogenicity; intraperitoneal infusion; malignant ascites; pharmacokinetics.

Figures

Figure 1

Individual (symbols) and median (–) catumaxomab ascites concentrations observed during the course of treatment. Intraperitoneal infusions are indicated by arrows. The third infusion (50 µg) was administered either on day 6 or 7. Ascites samples were taken immediately before the second, third, and fourth infusions. 108/102 (); 118/101 (); 805/101 (); 805/102 (); 805/103 (); 805/107 (); 805/108 (); 805/112 (); 805/113 (); 808/101 (); Median ()

Figure 2

Individual catumaxomab plasma concentration vs. time profiles in 10 patients. Intraperitoneal infusions of catumaxomab are indicated by arrows. The third (50 µg) infusion was administered either on day 6 or 7. Catumaxomab was detectable in the plasma only after the third and fourth infusions. 108/102 (); 118/101 (); 805/101 (); 805/102 (); 805/103 (); 805/107 (); 805/108 (); 805/112 (); 805/113 (); 808/101 ()

Figure 3

Bioactivity of catumaxomab in ascites and plasma samples. Bioactivity was determined in a potency assay that evaluated ascites and plasma samples for the abilities to A) kill EpCAM-positive HCT-8 tumour cells and B) secrete TNF-α cytokine, relative to controls with freshly spiked catumaxomab. Ascites samples were obtained before the third or fourth infusion from five patients, and two plasma samples were obtained from one patient

Figure 4

Anti-drug antibody response in plasma vs. time profiles in 10 patients within the first 3 weeks after the beginning of the treatment. 108/102 (); 118/101 (); 805/101 (); 805/102 (); 805/103 (); 805/107 (); 805/108 (); 805/112 (); 805/113 (); 808/101 ()