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Hu11B6 is a monoclonal antibody that internalizes in cells expressing androgen receptor (AR)-regulated prostate-specific enzyme human kallikrein-related peptidase 2 (hK2; KLK2). In multiple rodent models, Actinium-225-labeled hu11B6-IgG1 ([225Ac]hu11B6-IgG1) has shown promising treatment efficacy. In the present study, we investigated options to enhance and optimize [225Ac]hu11B6 treatment. First, we evaluated the possibility of exploiting IgG3, the IgG subclass with superior activation of complement and ability to mediate FC-γ-receptor binding, for immunotherapeutically enhanced hK2 targeted α-radioimmunotherapy. Second, we compared the therapeutic efficacy of a single high activity vs. fractionated activity. Finally, we used RNA sequencing to analyze the genomic signatures of prostate cancer that progressed after targeted α-therapy. [225Ac]hu11B6-IgG3 was a functionally enhanced alternative to [225Ac]hu11B6-IgG1 but offered no improvement of therapeutic efficacy. Progression-free survival was slightly increased with a single high activity compared to fractionated activity. Tumor-free animals succumbing after treatment revealed no evidence of treatment-associated toxicity. In addition to up-regulation of canonical aggressive prostate cancer genes, such as MMP7, ETV1, NTS, and SCHLAP1, we also noted a significant decrease in both KLK3 (prostate-specific antigen ) and FOLH1 (prostate-specific membrane antigen) but not in AR and KLK2, demonstrating efficacy of sequential [225Ac]hu11B6 in a mouse model.

PET PSMA imaging is a sufficient and potentially superior alternative to conventional imaging in the initial staging of newly diagnosed prostate cancer. As such, conventional imaging such as bone scan or CT is not considered a necessary pre-requisite to PET PSMA when staging patients. We investigated imaging results at our institution to better understand the contemporary role of conventional imaging. We retrospectively identified 79 patients with newly diagnosed prostate cancer who underwent initial staging with conventional imaging and Gallium-68 or F-18 piflufolastat (DCFPyL) PSMA PET/CT scan in our eleven hospital system from July 2021–December 2022. Sufficient conventional imaging was defined as a bone scan with at least one of either an MRI or CT scan. The reference standard for a positive scan included either histopathology demonstrating prostate adenocarcinoma or a change of a bone lesion to blastic on follow-up imaging. Cases were also considered positive if they met at least three soft criteria, including a corresponding positive lesion in a different imaging modality, increase in size or number of lesions over time, decrease in size or number of lesions after treatment, clinical symptoms of malignancy, localized treatment for imaging finding, PSA increase without treatment, PSA decrease with treatment, and typical appearance of multifocal disease. Equivocal findings were considered negative. PSMA PET/CT detected 93% (42/45) of total imaging positivity for patients who received both a PET scan and conventional imaging (Figure 1). PSMA PET/CT had a sensitivity of 100% and a specificity of 95% in our cohort. Comparatively, conventional imaging had a sensitivity of 76% and;specificity of 89% in our cohort. Detection rates by disease localization and imaging modality are shown in Figure 2. PSMA PET/CT falsely showed positivity for two patients, detecting both pelvic and distant nodal metastatic disease while only pelvic nodal disease was confirmed by our reference standard. Conventional imaging failed to detect cancer in 50% (9/18) of pelvic nodal disease, 60% (3/5) of distant nodal metastases, and 6% (1/16) of metastases to the bone. T99MDP bone scan only detected 63% (10/16) of metastases to the bone. When used, CT scan detected 50% (15/30) of positivity and MRI detected 50% (12/24) of positivity. PSMA PET/CT has higher specificity and sensitivity than conventional imaging for initial staging within our cohort. Real-world practice supports the omission of conventional imaging prior to PET PSMA in initial staging as it would not lead to additional detection of pelvic or metastatic cases. [ABSTRACT FROM AUTHOR]