Genetic signature of prostate cancer mouse models resistant to optimized hK2 targeted alpha-particle therapy
Menée sur des modèles murins de cancer de la prostate résistant à [225Ac]hu11B6, un anticorps conjugué émettant des particules alpha et ciblant la peptidase hK2, cette étude présente une stratégie, reposant notamment sur la recherche de signatures génétiques, pour identifier des mécanismes de résistance et améliorer l'efficacité du traitement
Molecularly targeted α-therapy is an emerging therapeutic option for prostate cancer patients. We previously developed [225Ac]hu11B6, an α-particle–emitting antibody conjugate, which specifically internalizes into prostate cancer cells by binding to human kallikrein-related peptidase 2. Here, we explore methods to enhance its therapeutic efficacy, prospective treatment strategies, and potential resistance mechanisms in preclinical models. We demonstrate that switching the antibody subclass to IgG3 can be applied to radioimmunotherapy and may enhance efficacy. Second, repeat [225Ac]hu11B6 administration is effective, even in tumors relapsing after initial treatment. Third genetic profiling revealed radio-biological mechanisms associated with relapse after α-radioimmunotherapy that could appropriate combination therapies. Our findings support the clinical translation of [225Ac]hu11B6 as a highly effective, urgently needed treatment option for prostate cancer.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.