Rosopatamab is a humanized monoclonal antibody targeting prostate-specific membrane antigen (PSMA) for the treatment of prostate cancer. It can be conjugated with radiolabeled isotopes (e.g., 177Lu) via DOTA-NHS ester to form radiopharmaceuticals for targeted therapy. In preclinical studies, 177Lu-DOTA-Rosopatamab combined with the DNA-PK inhibitor Peposertib achieved a 75% complete response rate in prostate cancer mouse models.

Methods: Tumors of mice bearing SK-RC-52 RCC or LNCaP prostate cancer xenografts were delivered beta-irradiated with 177Lu-DOTA-Girentuximab (targeting carbonic anhydrase IX) or 177Lu-DOTA-Rosopatamab (targeting prostate-specific membrane antigen) via a single intravenous dose (3 or 6 MBq), respectively. Mice were treated with peposertib (50 mg/kg, gavage, for 14 days). Biodistribution and in vivo imaging of 177Lu radioimmunotherapy were performed in both preclinical models. Tumor growth and body weight were monitored until endpoint. DNA damage was assessed by measuring DSBs by analyzing γH2AX foci formation in tumor sections.
Results: In vitro biodistribution and in vivo SPECT/MRI showed high tumor uptake of each radiopharmaceutical. Body weights of mice were stable in all treatment groups. Peposertib alone did not show significant antitumor effects. In the SK-RC-52 animal model, the addition of peposertib to 177Lu-DOTA-Girentuximab showed enhanced antitumor effects compared to 177Lu-DOTA-Girentuximab alone, with a complete remission rate of 4/4 in the 177Lu-DOTA-Girentuximab (6 MBq) plus peposertib group. The combination of peposertib with low-dose 177Lu-DOTA-Girentuximab (3 MBq) showed comparable antitumor activity to 177Lu-DOTA-Girentuximab (6 MBq) monotherapy. In the LNCaP prostate cancer model, the combination of 177Lu-DOTA-Rosopatamab (6 MBq) and peposertib achieved a complete remission rate of 3/4. Increased DSBs were observed after the addition of peposertib to 177Lu-based radioimmunotherapy. [1]