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
Notes: Article -- Export Date: 3 August 2020 -- Source: Scopus
Citation Impact
MSK Authors
  1. Michael Morris
    363 Morris
  2. Michael R Mcdevitt
    122 Mcdevitt
  3. Darren Veach
    64 Veach
  4. Hans Gosta Lilja
    307 Lilja