Due to copyright issues, an electronic copy of the thesis must be ordered from the faculty. For the faculty to have time to process the order, the order must be received by the faculty at the latest 2 days before the public defence. Orders received later than 2 days before the defence will not be processed. After the public defence, please address any inquiries regarding the thesis to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Katharina Lückerath, University of Duisburg-Essen, Germany
- Second opponent: Researcher Tom Bäck, University of Gothenburg, Sweden
- Third member and chair of the evaluation committee: Professor Marit Inngjerdingen, University of Oslo
Chair of the Defence
Professor II Kjersti Flatmark, University of Oslo
Principal Supervisor
Associate Professor Asta Juzeniene, University of Oslo
Summary
Cavitary malignancies, including malignant peritoneal mesothelioma, intraperitoneal ovarian cancer, and bladder cancer, represent challenging oncological conditions with poor prognoses. Untreated malignant peritoneal mesothelioma has a median survival of approximately 6 months, advanced ovarian carcinoma shows 5-year survival rates below 30% despite aggressive treatment, and high-risk bladder cancer results in recurrence, progression, or death in nearly three-quarters of patients within ten years.
Targeted alpha therapy with lead-212 (212Pb) represents a paradigm shift in radionuclide therapy, combining a manageable 10.6-hour half-life with potent cytotoxicity from alpha emissions via its daughter products. The anatomical confinement of cavitary cancers provides an ideal setting for locoregional 212Pb delivery.
This thesis evaluated two 212Pb-labeled monoclonal antibodies: anti-CD146 antibody OI-3 for malignant peritoneal mesothelioma and anti-PTK7 antibody OI-1 for ovarian and bladder cancers. Both antibodies demonstrated nanomolar binding affinity and efficient internalization kinetics. Radiochemical optimization established optimal TCMC conjugation ratios (5:1-10:1) that preserved immunoreactivity (50-65%) while ensuring high radiochemical purity (≥95%). Preclinical studies showed robust antitumor efficacy across multiple cavitary malignancy models. Intraperitoneal administration of 212Pb-TCMC-OI-3 significantly prolonged survival in mesothelioma-bearing mice (median 55 vs. 40 days, p<0.05) without observable toxicity. Similarly, 212Pb-TCMC-OI-1 exhibited significant tumor growth inhibition in ovarian cancer models with tumor-free fractions of 87.5-100% for treated animals. These findings demonstrate the potential of CD146 and PTK7 as therapeutic targets for 212Pb-based targeted alpha therapy, providing a foundation for potential clinical development.
Additional information
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