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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-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., Competing Interests: Competing interest statement: S.-E.S., A.-C.M.H., H.L., and D.U. are consultant/advisory board members for and hold ownership interest in Diaprost AB. S.-E.S. and D.U. are listed as coinventors on a several patents regarding the humanized form of 11B6, which is owned by Diaprost. C.G.R. is cofounder and holds equity in Sofie Biosciences and Trethera Therapeutics. Intellectual property has been patented by the University of California and has been licensed to Sofie Biosciences and Trethera Therapeutics. This intellectual property was not used in the present study. H.L. holds ownership interest (including patents) in OPKO Health, and reports other remuneration from OPKO Health. S.M.L. reports receiving commercial research grants from Regeneron and Telix, holds ownership interest (including patents) in Voreyda, Imaginab, and Elucida, and is a consultant/advisory board member for Johnson and Johnson. M.J.M. is a consultant/advisory board member for Bayer, Endocyte, Advanced Accelerator Applications, Blue Earth Diagnostics, Tolmar, and ORIC. Memorial Sloan Kettering Cancer Center has filed for IP protection for inventions related to α-particle technology of which M.R.M. is an inventor. M.R.M. was a consultant for Actinium Pharmaceuticals, Regeneron, Progenics, Bridge Medicines, and General Electric. M.E.P. is a cofounder and board member of Sofie Biosciences but does not hold ownership interest nor receive any funding from the company. M.E.P. also holds some ownership interest in InDi Molecular.