PHARMACOKINETICS, BIODISTRIBUTION AND BIOLOGICAL EFFECTS OF INTRAVENOUSLY ADMINISTERED BISPECIFIC MONOCLONAL-ANTIBODY OC TR F(AB')(2) IN OVARIAN-CARCINOMA PATIENTS/

The bispecific monoclonal antibody (biMAb) OC/TR combines the anti-ova rian-cancer reactivity of the MOv18 monoclonal antibody (MAb) with the reactivity of an anti-CD3 MAb. Pre-clinical studies have indicated th at this biMAb is able to redirect the cytolytic activity of T cells to wards tumour cells, resulting in efficient tumour-cell lysis. To asses s the clinical potential of systemic biMAb-based cancer therapy we ini tiated a study in ovarian-cancer patients. Five patients suspected of ovarian cancer received I-123-OC/TR F(ab')(2) i.v. Unexpectedly, the f irst patient developed side effects (grade Ill-IV toxicity) starting 3 0 min after infusion (p.i.) of 1 mg of OC/TR F(ab')(2). After approval of the Ethical Committee, the study was continued at lower dose level s (0.1 mg; 0.2 mg). However, at the 0.2-mg dose level similar side eff ects were observed. FACS analysis indicated that all peripheral T cell s were coated with biMAb immediately following the infusion. The cytok ines tumour necrosis factor-alpha, interferon-gamma and interleukin-2 showed maximum serum concentrations 2 h p.i. Tumour uptake ranged from 0.8 to 1.9% ID/kg, resulting in tumour/background ratios of 3 to 8. O ur results suggest that at higher antibody dose levels OC/TR F(ab')(2) causes T-cell activation with acute release of cytokines. Only low do ses of biMAb can be administered safely. Despite the interaction with T cells, OC/TR F(ab')(2) preferentially localizes in tumours following i.v. administration, thus offering therapeutic perspectives. (C) 1996 Wiley-Liss, Inc.