Abstract
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Objectives: Recently antibodies directed against the cell surface protein L1 were found to inhibit growth of target tumor cells in vitro and peritoneal growth and dissemination of SKOV3ip human ovarian carcinoma cells in vivo in nude mice (M.J.E. Arlt, I. Novak-Hofer, D. Gast et al, Cancer Res 66, 2006). The objective of our study was to investigate if the combination of antibody therapy with Cu-67-radioimmunotherapy increased the survival of nude mice with SKOV3ip ovarian cancer metastases.
Methods: An aglycosylated form of anti-L1 mAb chCE7 was engineered, produced in high amounts in HEK-293 cells, derivatized with the CPTA ligand and labeled with Cu-67. Groups of 8 mice were treated 2 days post i.p. injection of 5x106 SKOV3ip cells: Controls, Cu-67-CPTA-Lym1 control mAb (5 MBq, 157 µg) i.v., Cu-67-CPTA-chCE7agl (5 MBq, 213 µg) i.v., 10 mg/kg anti-L1 mAb 11A i.p. Cu-67-mAb treatment was a single dose, mAb 11A treatment continued biweekly. The endpoint when animals were euthanised was set to be visible ascites or >15% weight loss combined with behavioral signs of distress.
Results: Compared with mAb chCE7 the chCE7agl construct showed significantly decreased half life (beta-half life 96 h versus 138 h) in the blood, when in radioiodinated form. Blood clearance of the two mAb formats in Cu-67-labeled form was more rapid with a beta half life of 39 h for radiocopper labeled chCE7agl vs 79 h for radiocopper labeled chCE7. Biodistributions of Cu-67-CPTA-chCE7agl in groups of 4 nude mice with SKOV3ip metastases showed high tumor uptake and long tumor residence time. Five days post i.v. injection %ID/g values were for tumor 48.5±13, for blood 2.2±1.2 and for liver 3.1±0.9. Median survival of mice treated twice a week with just 10 mg/kg of mAb 11A, which targets a different L1 epitope than mAb chCE7, was found to be less than 38 days. After a single low dose (5 MBq) of Cu-67-chCE7agl median survival (34 days) was significantly different from untreated controls (29 days) and from non- target binding mAb Cu-67-Lym1 (31 days). The combination of Cu-67-chCE7agl with biweekly doses of mAb 11A increased median survival significantly further to 49 days.
Conclusions: The study shows proof of principle for combining radioactive and growth inhibiting anti-L1-CAM monoclonal antibodies for more efficient therapy of ovarian cancer.
Research Support (if any): Swiss National Science Foundation grant 3100A0-100200 (I.Novak-Hofer)
- Society of Nuclear Medicine, Inc.