In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 26 ( 2020-06-30), 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-IgG 1 ([ 225 Ac]hu11B6-IgG 1 ) has shown promising treatment efficacy. In the present study, we investigated options to enhance and optimize [ 225 Ac]hu11B6 treatment. First, we evaluated the possibility of exploiting IgG 3 , 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. [ 225 Ac]hu11B6-IgG 3 was a functionally enhanced alternative to [ 225 Ac]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 [ 225 Ac]hu11B6 in a mouse model.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1918744117
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2020
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
Bookmarklink