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Updated: Dec 18, 2025
Pre-clinical Orthotopic Murine Model of Human Prostate Cancer
Published on: August 29, 2016
Genetic signature of prostate cancer mouse models resistant to optimized hK2 targeted α-particle therapy
Mesude Bicak1, Katharina Lückerath2,3, Teja Kalidindi4
1Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genome Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
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.
Insights
This study optimized Actinium-225-labeled hu11B6 antibody treatments for prostate cancer. While IgG3 offered functional enhancement, a single high dose showed slightly better progression-free survival and reduced aggressive gene expression.
Area of Science:
- Oncology
- Immunotherapy
- Radiopharmaceuticals
Background:
- Hu11B6 is a monoclonal antibody targeting human kallikrein-related peptidase 2 (hK2) in prostate cancer cells.
- Actinium-225-labeled hu11B6-IgG1 ([225Ac]hu11B6-IgG1) demonstrated promising therapeutic efficacy in preclinical models.
- Optimizing targeted alpha radioimmunotherapy requires exploring antibody variants and dosing strategies.
Purpose of the Study:
- To evaluate IgG3 subclass for enhanced hK2-targeted alpha radioimmunotherapy.
- To compare the therapeutic efficacy of single high-dose versus fractionated dosing of [225Ac]hu11B6.
- To analyze genomic signatures of prostate cancer progression following targeted alpha therapy.
Main Methods:
- Utilized Actinium-225-labeled hu11B6-IgG3 and hu11B6-IgG1 in rodent models.
- Compared single high-activity administration versus fractionated activity dosing.
- Employed RNA sequencing to identify genomic alterations in progressed tumors.
Main Results:
- [225Ac]hu11B6-IgG3 showed functional enhancement but no improved therapeutic efficacy over IgG1.
- A single high activity dose resulted in slightly increased progression-free survival compared to fractionated dosing.
- No treatment-associated toxicity was observed in tumor-free animals.
- RNA sequencing revealed upregulation of aggressive prostate cancer genes (e.g., MMP7, ETV1) and downregulation of KLK3 and FOLH1, indicating treatment efficacy.
Conclusions:
- Actinium-225-labeled hu11B6-IgG3 is a functionally enhanced but not therapeutically superior alternative to IgG1.
- Single high-dose administration of [225Ac]hu11B6 may offer a slight survival benefit over fractionated dosing.
- Targeted alpha therapy with [225Ac]hu11B6 demonstrates efficacy by altering gene expression profiles in progressing prostate cancer.
