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Genetic signature of prostate cancer mouse models resistant to optimized hK2 targeted α-particle therapy.
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2020-06-30 , DOI: 10.1073/pnas.1918744117
Mesude Bicak 1 , Katharina Lückerath 2, 3 , Teja Kalidindi 4 , Michael E Phelps 5 , Sven-Erik Strand 6 , Michael J Morris 7 , Caius G Radu 2, 3, 8 , Robert Damoiseaux 2 , Mari T Peltola 9 , Norbert Peekhaus 2 , Austin Ho 2 , Darren Veach 4, 10, 11 , Ann-Christin Malmborg Hager 11 , Steven M Larson 4, 12 , Hans Lilja 7, 13, 14, 15, 16 , Michael R McDevitt 4, 12 , Robert J Klein 17 , David Ulmert 3, 5, 8, 18
Affiliation  

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.



中文翻译:


对优化的 hK2 靶向 α 粒子治疗产生耐药性的前列腺癌小鼠模型的遗传特征。



Hu11B6 是一种单克隆抗体,可内化于表达雄激素受体 (AR) 调节的前列腺特异性酶人激肽释放酶相关肽酶 2 (hK2; KLK2 ) 的细胞中。在多种啮齿动物模型中,Actinium-225 标记的 hu11B6-IgG 1 ([ 225 Ac]hu11B6-IgG 1 ) 显示出良好的治疗效果。在本研究中,我们研究了增强和优化[ 225 Ac]hu11B6 治疗的方案。首先,我们评估了利用 IgG 3进行免疫治疗增强 hK2 靶向 α-放射免疫治疗的可能性,IgG 3 是一种具有出色的补体激活能力和介导 FC-γ-受体结合能力的 IgG 亚类。其次,我们比较了单一高活性与分段活性的治疗效果。最后,我们使用 RNA 测序来分析靶向 α 疗法后进展的前列腺癌的基因组特征。 [ 225 Ac]hu11B6-IgG 3是 [ 225 Ac]hu11B6-IgG 1的功能增强替代品,但没有改善治疗效果。与分段活动相比,单次高活动的无进展生存期略有增加。治疗后死亡的无肿瘤动物没有发现与治疗相关的毒性的证据。 除了典型的侵袭性前列腺癌基因(例如MMP7ETV1NTSSCHLAP1 )上调外,我们还注意到KLK3 (前列腺特异性抗原)和FOLH1 (前列腺特异性膜抗原)均显着减少,但没有显着减少。在ARKLK2中,证明了连续 [ 225 Ac]hu11B6 在小鼠模型中的功效。

更新日期:2020-06-30
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