학술논문
Genetic signature of prostate cancer mouse models resistant to optimized hK2 targeted α-particle therapy
Document Type
article
Author
Bicak, Mesude; Lückerath, Katharina; Kalidindi, Teja; Phelps, Michael E; Strand, Sven-Erik; Morris, Michael J; Radu, Caius G; Damoiseaux, Robert; Peltola, Mari T; Peekhaus, Norbert; Ho, Austin; Veach, Darren; Malmborg Hager, Ann-Christin; Larson, Steven M; Lilja, Hans; McDevitt, Michael R; Klein, Robert J; Ulmert, David
Source
Proceedings of the National Academy of Sciences of the United States of America. 117(26)
Subject
Language
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.