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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Mesude Bicak
  • Katharina Lückerath
  • Teja Kalidindi
  • Michael E. Phelps
  • Sven Erik Strand
  • Michael J. Morris
  • Caius G. Radu
  • Robert Damoiseaux
  • Mari T. Peltola
  • Norbert Peekhaus
  • Austin Ho
  • Darren Veach
  • Ann Christin Malmborg Hager
  • Steven M. Larson
  • Hans Lilja
  • Michael R. McDevitt
  • Robert J. Klein
  • David Ulmert
Organisations
External organisations
  • Icahn School of Medicine at Mount Sinai
  • University of California, Los Angeles
  • Memorial Sloan-Kettering Cancer Center
  • University of Turku
  • University of Oxford
  • Diaprost AB
  • Cornell University
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
  • Cancer and Oncology

Keywords

  • 225Ac, hK2, hu11B6, prostate cancer, radiommunotherapy
Original languageEnglish
Pages (from-to)15172-15181
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number26
Publication statusPublished - 2020
Publication categoryResearch
Peer-reviewedYes