1. Genetic signature of prostate cancer mouse models resistant to optimized hK2 targeted α-particle therapy.
- Author
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Bicak, Mesude, Lückerath, Katharina, Kalidindi, Teja, Phelps, Michael E., Strand, Sven-Erik, Morris, Michael J., Radu, Caius G., Damoiseaux, Robert, Peltola, Mari T., Peekhaus, Norbert, Ho, Austin, Veach, Darren, Hager, Ann-Christin Malmborg, Larson, Steven M., Lilja, Hans, McDevitt, Michael R., Klein, Robert J., and Ulmert, David
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PROSTATE cancer ,TREATMENT effectiveness ,PROSTATE-specific antigen ,ANDROGEN receptors ,CANCER genes - 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 ([
225 Ac]hu11B6-IgG1) 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 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. [225 Ac]hu11B6-IgG2 was a functionally enhanced alternative to [225 Ac]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 [225 Ac]hu11B6 in a mouse model. [ABSTRACT FROM AUTHOR]- Published
- 2020
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