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

Abstract

AIMSCatumaxomab is the first EMEA approved trifunctional anti-EpCAM×anti-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.METHODSThirteen cancer patients with symptomatic malignant ascites were treated with four ascending doses of 10, 20, 50, and 150 µg 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.RESULTSTen 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 (Cmax) 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.CONCLUSIONSBased 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.

Transient lymphocyte decrease due to adhesion and migration following catumaxomab (anti-EpCAM x anti-CD3) treatment in vivo

“…T cell activation was observed starting at the lowest concentration of catumaxomab studied (2 ng/ ml) and an increase in cytokine release was observed at catumaxomab in vitro concentrations from 0.1 ng/ml. This is in accordance with previous in vitro studies which underline that catumaxomab activates PBMC and stimulates the release of cytokines, including TNF and IFN, from human blood cells in the presence of target tumour cells [12][13][14][15] as part of its mode of action. Release of TNF and IFN peaked at 24 h [14].…”

Efficacy and Tolerability of a GD2-Directed Trifunctional Bispecific Antibody in a Preclinical Model: Subcutaneous Administration Is Superior to Intravenous Delivery

“…TrAbs, which recruit different types of immune effector cells to the tumor cells and thereby also induce a T-cell memory (6,7), are one of the most potent immunologic antitumor reagents hitherto used in cancer patients. These Ig constructs, which are effective at nanogram/mL concentrations (18,27), may raise particular safety concerns (18,19). Although trAb-induced cytokine-related adverse events are manageable in the clinics by using low starting doses and subsequent dose escalation (18,28), there must be constant efforts to further improve patients' safety thus increasing the treatment options for trAbs in the near future.…”

A Novel Carcinoembryonic Antigen T-Cell Bispecific Antibody (CEA TCB) for the Treatment of Solid Tumors

“…A major limitation of the earlier TCB molecules was that they induced strong cytokine release and resulted in severe infusion-related reactions, which precluded their systemic administration. Indeed such an earlier TCB, catumaxomab, targeting EpCAM, could only be applied for local, peritoneal administration for the treatment of malignant ascites (6). Besides being highly immunogenic in humans (as rat/mouse hybrid monoclonal antibody), catumaxomab carries an active Fc domain capable of crosslinking FcgRs on innate immune cells and CD3e on T cells, which leads to strong cytokine release upon systemic administration, independently of tumor target cell binding (7).…”