Pharmacokinetics, biodistribution and biological effects of intravenously administered bispecific monoclonal antibody OC/TR F(ab′)2 in ovarian carcinoma patients

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Abstract
The bispecific monoclonal antibody (biMAb) OC/TR combines the anti‐ovarian‐cancer reactivity of the MOv18 monoclonal antibody (MAb) with the reactivity of an anti‐CD3 MAb. Pre‐clinical studies have indicated that this biMAb is able to redirect the cytolytic activity of T cells towards tumour cells, resulting in efficient tumour‐cell lysis. To assess the clinical potential of systemic biMAb‐based cancer therapy we initiated a study in ovarian‐cancer patients. Five patients suspected of ovarian cancer received 123I‐OC/TR F(ab′)2 i.v. Unexpectedly, the first patient developed side effects (grade III–IV toxicity) starting 30 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 levels (0.1 mg; 0.2 mg). However, at the 0.2‐mg dose level similar side effects were observed. FACS analysis indicated that all peripheral T cells were coated with biMAb immediately following the infusion. The cytokines tumour necrosis factor‐α, interferon‐γ 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. Our results suggest that at higher antibody dose levels OC/TR F(ab′)2 causes T‐cell activation with acute release of cytokines. Only low doses 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.

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