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Genetic signature of prostate cancer mouse models resistant to optimized hK2 targeted α-particle therapy

Bicak, Mesude ; Lückerath, Katharina ; Kalidindi, Teja ; Phelps, Michael E. ; Strand, Sven Erik LU ; Morris, Michael J. ; Radu, Caius G. ; Damoiseaux, Robert ; Peltola, Mari T. and Peekhaus, Norbert , et al. (2020) In Proceedings of the National Academy of Sciences of the United States of America 117(26). p.15172-15181
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
225Ac, hK2, hu11B6, prostate cancer, radiommunotherapy
in
Proceedings of the National Academy of Sciences of the United States of America
volume
117
issue
26
pages
10 pages
publisher
National Academy of Sciences
external identifiers
  • scopus:85087466007
  • pmid:32532924
ISSN
1091-6490
DOI
10.1073/pnas.1918744117
language
English
LU publication?
yes
id
d9e979bd-51e7-42c2-8c18-ab3712b435e6
date added to LUP
2020-07-16 10:21:50
date last changed
2023-04-10 16:53:14
@article{d9e979bd-51e7-42c2-8c18-ab3712b435e6,
  abstract     = {{<p>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.</p>}},
  author       = {{Bicak, Mesude and Lückerath, Katharina and Kalidindi, Teja and Phelps, Michael E. and Strand, Sven Erik and Morris, Michael J. and Radu, Caius G. and Damoiseaux, Robert and Peltola, Mari T. and Peekhaus, Norbert and Ho, Austin and Veach, Darren and Malmborg Hager, Ann Christin and Larson, Steven M. and Lilja, Hans and McDevitt, Michael R. and Klein, Robert J. and Ulmert, David}},
  issn         = {{1091-6490}},
  keywords     = {{225Ac; hK2; hu11B6; prostate cancer; radiommunotherapy}},
  language     = {{eng}},
  number       = {{26}},
  pages        = {{15172--15181}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences of the United States of America}},
  title        = {{Genetic signature of prostate cancer mouse models resistant to optimized hK2 targeted α-particle therapy}},
  url          = {{http://dx.doi.org/10.1073/pnas.1918744117}},
  doi          = {{10.1073/pnas.1918744117}},
  volume       = {{117}},
  year         = {{2020}},
}