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

: Bicak M, Luckerath K, Kalidindi T, Phelps ME, Strand SE, Morris MJ, Radu CG, Damoiseaux R, Peltola MT, Peekhaus N, Ho A, Veach D, Hager ACM, Larson SM, Lilja H, McDevitt MR, Klein RJ, Ulmert D

Publisher: NATL ACAD SCIENCES

: 2020

Proceedings of the National Academy of Sciences of the United States of America

: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

: P NATL ACAD SCI USA

: 117

: 26

: 15172

: 15181

: 10

: 0027-8424

: 1091-6490

DOI: https://doi.org/10.1073/pnas.1918744117

: https://www.pnas.org/content/117/26/15172

: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334567/

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-IgG(1) ([Ac-225]hu11B6-IgG(1)) has shown promising treatment efficacy. In the present study, we investigated options to enhance and optimize [Ac-225]hu11B6 treatment. First, we evaluated the possibility of exploiting IgG(3), the IgG subclass with superior activation of complement and ability to mediate FC-gamma-receptor binding, for immunotherapeutically enhanced hK2 targeted alpha-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 alpha-therapy. [Ac-225]hu11B6-IgG(3) was a functionally enhanced alternative to [Ac-225]hu11B6-IgG(1) 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 [Ac-225]hu11B6 in a mouse model.