title: Pharmacokinetics, immunogenicity and bioactivity of the therapeutic antibody catumaxomab intraperitoneally administered to cancer patients.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Antibody Development, TRION Research GmbH, Am Klopferspitz 19, 82152 Martinsried, Germany. peter.ruf@trionresearch.de
authors.forename: Peter
authors.initials: P
authors.lastname: Ruf
authors.forename: Michael
authors.initials: M
authors.lastname: Kluge
authors.forename: Michael
authors.initials: M
authors.lastname: Jäger
authors.forename: Alexander
authors.initials: A
authors.lastname: Burges
authors.forename: Constantin
authors.initials: C
authors.lastname: Volovat
authors.forename: Markus Maria
authors.initials: MM
authors.lastname: Heiss
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hess
authors.forename: Pauline
authors.initials: P
authors.lastname: Wimberger
authors.forename: Birgit
authors.initials: B
authors.lastname: Brandt
authors.forename: Horst
authors.initials: H
authors.lastname: Lindhofer
mesh_terms: D018033:Antibodies, Bispecific / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics*; D000911:Antibodies, Monoclonal / Q000097:blood; D001201:Ascites / Q000378:metabolism; D001682:Biological Availability; D016207:Cytokines / Q000032:analysis; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006801:Humans; D007155:Immunologic Factors / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics*; D007274:Injections, Intraperitoneal; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D016207:Cytokines; D007155:Immunologic Factors; C522419:catumaxomab