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

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-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. 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.

• Authors: J G Tibben, O C Boerman, L F Massuger, C P Schijf, R A Claessens, F H Corstens
• Journal: International journal of cancer (Int J Cancer) Vol. 66 Issue 4 Pg. 477-83 (May 16 1996) ISSN: 0020-7136 [Print] United States
• PMID: 8635863 (Publication Type: Clinical Trial, Journal Article)

Chemical References

• Antibodies, Bispecific
• Antibodies, Monoclonal
• CD3 Complex
• Carrier Proteins
• Folate Receptors, GPI-Anchored
• Immunoglobulin Fab Fragments
• Receptors, Cell Surface
• Tumor Necrosis Factor-alpha

Topics

• Adenocarcinoma (diagnostic imaging, therapy)
• Antibodies, Bispecific (administration & dosage, adverse effects, metabolism, pharmacokinetics)
• Antibodies, Monoclonal (administration & dosage, adverse effects, metabolism, pharmacokinetics)
• CD3 Complex (immunology)
• Carrier Proteins (immunology)
• Cystadenoma (therapy)
• Dose-Response Relationship, Immunologic
• Female
• Folate Receptors, GPI-Anchored
• Humans
• Immunoglobulin Fab Fragments (metabolism)
• Immunotherapy
• Infusions, Intravenous
• Ovarian Neoplasms (diagnostic imaging, therapy)
• Radionuclide Imaging
• Receptors, Cell Surface
• Tissue Distribution
• Tumor Necrosis Factor-alpha (metabolism)