Dickkopf-1 (DKK1), a secreted modulator of Wnt signaling, is overexpressed in many cancers, is often associated with worse clinical outcomes, and has been shown to have immunosuppressive effects. DKN-01 is an IgG4 clinical stage antibody that potently and specifically neutralizes human and murine DKK1 and has recently completed a promising study in combination with pembrolizumab in gastric/gastroesophageal junction cancer patients. The purpose of the current study is to characterize a murine version of DKN-01 (mDKN-01) and to better understand its mechanism of action. We examined the efficacy of mDKN-01 in both melanoma and metastatic breast cancer models. Immune depletion experiments revealed a requirement for NK but not B and T-cells for tumor growth inhibition. mDKN-01 treatment promotes the induction of the natural killer (NK)-activating cytokines Interleukin-15 (IL-15) and Interleukin-33 (IL-33) as well as an enhanced recruitment of CD45+ cells. Other treatment-related changes include a reduction of Gr-1+CD11b+ myeloid-derived suppressor cells (MDSCs) in the tumor and spleen and the up-regulation of PD-L1 on MDSCs. Additionally, mDKN-01 has a marked effect at reducing pulmonary metastases in the mouse 4T1 breast cancer model. Finally, the mDKN-01/anti-PD-1 combination was more effective at inhibiting melanoma growth than mDKN-01 alone. Taken together, our data demonstrate that mDKN-01 has efficacy by blocking the immunosuppressive effects of DKK1 in the tumor microenvironment and provides insight into the clinical activity observed with DKN-01 based treatment. Implications: mDKN-01 reverses a DKK1-mediated innate immune suppression in the tumor microenvironment and has additive efficacy with a PD-1 inhibitor.

中文翻译：

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mDKN-01，一种新型抗 DKK1 单克隆抗体，可增强肿瘤微环境中的先天免疫反应

Dickkopf-1 (DKK1) 是一种 Wnt 信号的分泌调节剂，在许多癌症中过度表达，通常与较差的临床结果相关，并且已被证明具有免疫抑制作用。DKN-01 是一种 IgG4 临床阶段抗体，可有效且特异性地中和人和鼠 DKK1，最近完成了一项与 pembrolizumab 联合用于胃/胃食管结合部癌患者的有希望的研究。当前研究的目的是表征鼠类 DKN-01 (mDKN-01) 并更好地了解其作用机制。我们检查了 mDKN-01 在黑色素瘤和转移性乳腺癌模型中的功效。免疫耗竭实验揭示了抑制肿瘤生长需要 NK 而不是 B 和 T 细胞。mDKN-01 治疗促进自然杀伤 (NK) 激活细胞因子白细胞介素 15 (IL-15) 和白细胞介素 33 (IL-33) 的诱导以及 CD45+ 细胞的增强募集。其他与治疗相关的变化包括肿瘤和脾脏中 Gr-1+CD11b+ 髓源性抑制细胞 (MDSC) 的减少以及 MDSC 上 PD-L1 的上调。此外，mDKN-01 在减少小鼠 4T1 乳腺癌模型中的肺转移方面具有显着效果。最后，mDKN-01/anti-PD-1 组合在抑制黑色素瘤生长方面比单独使用 mDKN-01 更有效。总之，我们的数据表明 mDKN-01 通过阻断 DKK1 在肿瘤微环境中的免疫抑制作用具有疗效，并提供了对基于 DKN-01 的治疗观察到的临床活性的洞察。影响：