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.

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MMP7 、 ETV1 、 NTS和SCHLAP1 ）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AR和KLK2中，证明了连续 [ ²²⁵ Ac]hu11B6 在小鼠模型中的功效。