scholarly journals Genetic signature of prostate cancer resistant to optimized hK2 targeted alpha-particle therapy

2019 ◽  
Author(s):  
Mesude Bicak ◽  
Katharina Lückerath ◽  
Teja Kalidindi ◽  
Sven-Erik Strand ◽  
Michael Morris ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Activity ◽  
Therapeutic Efficacy ◽  
Progression Free Survival ◽  
Particle Therapy ◽  
Cancer Genes ◽  
Genomic Signatures ◽  
Gamma Receptor ◽  
Human Kallikrein 2 ◽  
Kallikrein 2

AbstractHu11B6 is a monoclonal antibody that internalizes in cells expressing androgen receptor (AR)-regulated prostate specific enzyme human kallikrein 2 (hK2; KLK2). In multiple rodent models, Actinium-225 labeled hu11B6-IgG1 ([225Ac]hu11B6-IgG1) has shown promising treatment efficacy. In the current study we investigated options to enhance and optimize [225Ac]hu11B6 treatment. Firstly, we evaluated the possibility of exploiting IgG3, the immunoglobulin G (IgG) subclass with superior activation of complement and ability to mediate FC-gamma-receptor binding, for immunotherapeutically enhanced hK2 targeted alpha-radioimmunotherapy. Secondly, 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. [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 upregulation of canonical aggressive prostate cancer genes, such as MMP7, ETV1, NTS and SCHLAP1, we also noted a significant decrease in both KLK3 (PSA) and FOLH1 (PSMA) but not in AR and KLK2, demonstrating efficacy of sequential [225Ac]hu11B6 in a mouse model.

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

2020 ◽  
Vol 117 (26) ◽  
pp. 15172-15181 ◽  
Author(s):  
Mesude Bicak ◽  
Katharina Lückerath ◽  
Teja Kalidindi ◽  
Michael E. Phelps ◽  
Sven-Erik Strand ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Activity ◽  
Therapeutic Efficacy ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Particle Therapy ◽  
Cancer Genes ◽  
Free Survival ◽  
Genomic Signatures ◽  
Promising Treatment

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-IgG3was a functionally enhanced alternative to [225Ac]hu11B6-IgG1but 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 asMMP7,ETV1,NTS, andSCHLAP1, we also noted a significant decrease in bothKLK3(prostate-specific antigen ) andFOLH1(prostate-specific membrane antigen) but not inARandKLK2, demonstrating efficacy of sequential [225Ac]hu11B6 in a mouse model.

815: Human Kallikrein 2 (HK2) Inhibitors Suppress Tumor Growth of Prostate Cancer Xenografts in Nude Mice

2006 ◽  
Vol 175 (4S) ◽  
pp. 263-263
Author(s):  
Christoph Kündig ◽  
Sylvain M. Cloutier ◽  
Steve Aellen ◽  
Loyse M. Felber ◽  
Jair R. Chagas ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Growth ◽  
Nude Mice ◽  
Human Kallikrein 2 ◽  
Kallikrein 2

scholarly journals Development of Sensitive Immunoassays for Free and Total Human Glandular Kallikrein 2

2004 ◽  
Vol 50 (9) ◽  
pp. 1607-1617 ◽  
Author(s):  
Ville Väisänen ◽  
Susann Eriksson ◽  
Kaisa K Ivaska ◽  
Hans Lilja ◽  
Martti Nurmi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Detection Limit ◽  
Solid Phase ◽  
Specific Antigen ◽  
Control Group ◽  
Serum Samples ◽  
Human Kallikrein 2 ◽  
Kallikrein 2 ◽  
Capture Antibody ◽  
Total Psa

Abstract Background: Free and total human kallikrein 2 (hK2) might improve the discrimination between prostate cancer and benign prostatic hyperplasia. Concentrations of hK2 are 100-fold lower than concentrations of prostate-specific antigen (PSA); therefore, an hK2 assay must have a low detection limit and good specificity. Methods: PSA- and hK2-specific monoclonal antibodies were used in solid-phase, two-site immunofluorometric assays to detect free and total hK2. The total hK2 assay used PSA-specific antibodies to block nonspecific signal. The capture antibody of the free hK2 assay did not cross-react with PSA. To determine the hK2 concentrations in the male bloodstream, total hK2 was measured in a control group consisting of 426 noncharacterized serum samples. Free and total hK2 were measured in plasma from 103 patients with confirmed prostate cancer. Results: All 426 males in the control group had a total hK2 concentration above the detection limit of 0.0008 μg/L. The median total hK2 concentration was 0.022 μg/L (range, 0.0015–0.37 μg/L). hK2 concentrations were 0.1–58% of total PSA (median, 3.6%). hK2 concentrations were similar in men 41–50 and 51–60 years of age. The ratio of hK2 to PSA steadily decreased from 5–30% at PSA <1 μg/L to 1–2% at higher PSA concentrations. In 103 patients with prostate cancer, the median hK2 concentration in plasma was 0.079 μg/L (range, 0.0015–16.2 μg/L). The median free hK2 concentration was 0.070 (range, 0.005–12.2) μg/L. The proportion of free to total hK2 varied from 17% to 131% (mean, 85%). Conclusions: The wide variation in the free-to-total hK2 ratio suggests that hK2 in blood plasma is not consistently in the free, noncomplexed form in patients with prostate cancer. The new assay is sufficiently sensitive to be used to study the diagnostic accuracies of free and total hK2 for prostate cancer.

The value of (−7, −5)pro-prostate-specific antigen and human kallikrein-2 as serum markers for grading prostate cancer

2004 ◽  
Vol 93 (6) ◽  
pp. 720-724 ◽  
Author(s):  
C.H. Bangma ◽  
M.F. Wildhagen ◽  
G. Yurdakul ◽  
F.H. Schröder ◽  
B.G. Blijenberg
Keyword(s):  
Prostate Cancer ◽  
Prostate Specific Antigen ◽  
Specific Antigen ◽  
Serum Markers ◽  
Human Kallikrein 2 ◽  
Kallikrein 2

scholarly journals Association of Polymorphism rs198977 in Human Kallikrein-2 Gene (KLK2) with Susceptibility of Prostate Cancer: A Meta-Analysis

PLoS ONE ◽  
2013 ◽  
Vol 8 (6) ◽  
pp. e65651
Author(s):  
Lishan Wang ◽  
Weidong Zang ◽  
Yunxia Sang ◽  
Dongli Xie ◽  
Li Wei ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Meta Analysis ◽  
Human Kallikrein 2 ◽  
Kallikrein 2

scholarly journals A Highly Sensitive Porous Silicon (P-Si)-Based Human Kallikrein 2 (hK2) Immunoassay Platform toward Accurate Diagnosis of Prostate Cancer

Sensors ◽  
2015 ◽  
Vol 15 (5) ◽  
pp. 11972-11987 ◽  
Author(s):  
Sang Lee ◽  
Kazuo Hosokawa ◽  
Soyoun Kim ◽  
Ok Jeong ◽  
Hans Lilja ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Porous Silicon ◽  
Accurate Diagnosis ◽  
Highly Sensitive ◽  
Human Kallikrein 2 ◽  
Kallikrein 2

700 TOTAL HUMAN KALLIKREIN 2 - A POTENTIALLY USEFUL SERUM MARKER OF BONE METASTASIS AND BIOCHEMICAL FAILURE IN PROSTATE CANCER

2009 ◽  
Vol 8 (4) ◽  
pp. 295 ◽  
Author(s):  
J. Phillips ◽  
C.L. Eaton ◽  
L. Proctor ◽  
D. Sokhi ◽  
A. Cronin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Serum Marker ◽  
Biochemical Failure ◽  
Human Kallikrein 2 ◽  
Kallikrein 2
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