These differences in radiobiology and pharmacokinetics mean that treatment intervals used for lutetium-177-based therapy cannot be assumed to apply to lead-212 radiopharmaceuticals. A central question in the development of lead-212 PSMA therapies is how treatment scheduling influences therapeutic effect. In this study, conducted in close collaboration with ARTBIO, the investigation focused on how treatment interval, per-cycle activity, and the number of repeated administrations affect the anti-tumour efficacy of the novel PSMA-targeting radioligand [212Pb]Pb-AB001 in a PSMA-expressing prostate cancer xenograft model.
Using PSMA-positive PC-3 PIP subcutaneous tumour xenografts, [212Pb]Pb-AB001 was evaluated across a range of treatment regimens. Cumulative administered activities from 0.8 to 1.6 MBq were divided into one to four cycles and delivered at 3-day, 7-day or 14-day intervals. Therapeutic response was assessed by measuring tumour growth delay and survival, and radioligand uptake was quantified after repeated administrations to determine whether tumour targeting remained maintained. Histological analyses were performed to evaluate tumour necrosis, stromal and vascular changes, and expression of PSMA and VEGF. Toxicity was assessed through body weight monitoring, organ weights, haematology, and clinical biochemistry.
The results showed that treatment scheduling had a substantial impact on therapeutic outcome in this model. When the same cumulative activity was divided into multiple administrations, weekly treatment produced more durable tumour control and longer survival than biweekly treatment. Increasing the per-cycle activity to 0.4 MBq and extending therapy to three or four weekly cycles yielded the most pronounced antitumour effects, and one third of the mice receiving four weekly cycles achieved complete tumour regression. In contrast, shortening the interval to every third day did not enhance efficacy and resulted in less favourable tumour control, despite the short physical half-life of lead-212. Although the study was not designed to define mechanistic explanations, the findings indicate that very frequent dosing is not necessarily beneficial in this setting and that the spacing between cycles influences how effectively repeated administrations contribute to tumour control.
Radioligand uptake studies showed that tumour accumulation of [212Pb]Pb-AB001 remained stable across repeated administrations, indicating that tumour targeting was preserved throughout multi-cycle treatment. Histological analysis supported the therapeutic findings. With repeated weekly injections, tumours showed progressively increased necrosis, oedema, stromal disruption, and a reduction in PSMA and VEGF expression, consistent with cumulative tissue damage. All treatment schedules were well tolerated. Body weight remained stable, and there were no meaningful changes in organ weights, clinical biochemistry or haematology. Cumulative administered activities up to 1.6 MBq did not produce detectable systemic toxicity in this model. To our knowledge, no comparable preclinical study has been performed for lutetium-177 PSMA radioligands, and there are no published data systematically evaluating treatment interval, cycle number or cumulative activity in a controlled and head-to-head manner. This underscores the novelty of this work and highlights an evidence gap that this study begins to address for lead-212-based radiopharmaceuticals.
A cautious interpretation is needed when considering how these mouse data may relate to clinical treatment planning, since PC-3 PIP tumours grow far more quickly than human prostate cancer. The weekly regimen that performed best in mice, therefore, cannot be viewed as a guide for human intervals. What the study does show is that repeated administration of a lead-212 PSMA radiopharmaceutical is more effective than a single dose in this model, and that the spacing between cycles influences the overall response. The study provides evidence that scheduling is an important variable for lead-212 PSMA therapy and offers a strong preclinical basis for further investigation of fractionated dosing in clinical studies.
Written by: Anna Julie Kjøl Høyvik,1,2,3 Vilde Yuli Stenberg,1,2 Rugile Liukaityte,1,2 Ada Repetto-Llamazares,2 Qian Peng,4 Rina Wangen-Riise,1 Elisabeth Wiig,1 Li-Wei Ma,1 Mona-Elisabeth Revheim,3,5 Asta Juzeniene,1,6
- Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
- ARTBIO AS, Oslo, Norway.
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
- Department of Pathology, Oslo University Hospital, Oslo, Norway.
- Intervention Centre, Oslo University Hospital, Oslo, Norway.
- Department of Physics, University of Oslo, Oslo, Norway.