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-IgG ₁ ([ ²²⁵ Ac]hu11B6-IgG ₁ ) has shown promising treatment efficacy. In the present study, we investigated options to enhance and optimize [ ²²⁵ Ac]hu11B6 treatment. First, we evaluated the possibility of exploiting IgG ₃ , 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. [ ²²⁵ Ac]hu11B6-IgG ₃ was a functionally enhanced alternative to [ ²²⁵ Ac]hu11B6-IgG ₁ 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 [ ²²⁵ Ac]hu11B6 in a mouse model.