Genetic signature of prostate cancer mouse models resistant to optimized hK2 targeted α-particle therapy

Abstract

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-IgG3was a functionally enhanced alternative to [225Ac]hu11B6-IgG1but 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 asMMP7,ETV1,NTS, andSCHLAP1, we also noted a significant decrease in bothKLK3(prostate-specific antigen ) andFOLH1(prostate-specific membrane antigen) but not inARandKLK2, demonstrating efficacy of sequential [225Ac]hu11B6 in a mouse model.