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-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.
Tibben
J G
JG
Department of Obstetrics and Gynaecology, University Hospital Nijmegen St. Radboud, The Netherlands.
Boerman
O C
OC
Massuger
L F
LF
Schijf
C P
CP
Claessens
R A
RA
Corstens
F H
FH
D000230:Adenocarcinoma / Q000000981:diagnostic imaging / Q000628:therapy*; D018033:Antibodies, Bispecific / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics; D017252:CD3 Complex / Q000276:immunology; D002352:Carrier Proteins / Q000276:immunology*; D003537:Cystadenoma / Q000628:therapy; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism; D007167:Immunotherapy; D007262:Infusions, Intravenous; D010051:Ovarian Neoplasms / Q000000981:diagnostic imaging / Q000628:therapy*; D011877:Radionuclide Imaging; D011956:Receptors, Cell Surface; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D007140:Immunoglobulin Fab Fragments; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha