Genetic signature of prostate cancer mouse models resistant to optimized hK2 targeted α-particle therapy Journal Article
| Authors: | Bicak, M.; Lückerath, K.; Kalidindi, T.; Phelps, M. E.; Strand, S. E.; Morris, M. J.; Radu, C. G.; Damoiseaux, R.; Peltola, M. T.; Peekhaus, N.; Ho, A.; Veach, D.; Malmborg Hager, A. C.; Larson, S. M.; Lilja, H.; McDevitt, M. R.; Klein, R. J.; Ulmert, D. |
| Article Title: | 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-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. |
| Keywords: | prostate cancer; 225ac; hk2; hu11b6; radiommunotherapy |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 117 |
| Issue: | 26 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2020-06-30 |
| Start Page: | 15172 |
| End Page: | 15181 |
| Language: | English |
| DOI: | 10.1073/pnas.1918744117 |
| PUBMED: | 32532924 |
| PROVIDER: | scopus |
| PMCID: | PMC7334567 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 August 2020 -- Source: Scopus |
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