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; <i>KLK2</i>). 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 <i>MMP7</i>, <i>ETV1</i>, <i>NTS</i>, and <i>SCHLAP1</i>, we also noted a significant decrease in both <i>KLK3</i> (prostate-specific antigen ) and <i>FOLH1</i> (prostate-specific membrane antigen) but not in <i>AR</i> and <i>KLK2</i>, demonstrating efficacy of sequential [²²⁵Ac]hu11B6 in a mouse model.