Guanylyl cyclase C (GCC) is a unique therapeutic target with expression restricted to the apical side of epithelial cell tight junctions thought to be only accessible by intravenously administered agents on malignant tissues where GCC expression is aberrant. In this study, we sought to evaluate the therapeutic potential of a second-generation investigational antibody–dug conjugate (ADC), TAK-164, comprised of a human anti-GCC mAb conjugated via a peptide linker to the highly cytotoxic DNA alkylator, DGN549. The in vitro binding, payload release, and in vitro activity of TAK-164 was characterized motivating in vivo evaluation. The efficacy of TAK-164 and the relationship to exposure, pharmacodynamic marker activation, and biodistribution was evaluated in xenograft models and primary human tumor xenograft (PHTX) models. We demonstrate TAK-164 selectively binds to, is internalized by, and has potent cytotoxic effects against GCC-expressing cells in vitro. A single intravenous administration of TAK-164 (0.76 mg/kg) resulted in significant growth rate inhibition in PHTX models of metastatic colorectal cancer. Furthermore, imaging studies characterized TAK-164 uptake and activity and showed positive relationships between GCC expression and tumor uptake which correlated with antitumor activity. Collectively, our data suggest that TAK-164 is highly active in multiple GCC-positive tumors including those refractory to TAK-264, a GCC-targeted auristatin ADC. A strong relationship between uptake of 89Zr-labeled TAK-164, levels of GCC expression and, most notably, response to TAK-164 therapy in GCC-expressing xenografts and PHTX models. These data supported the clinical development of TAK-164 as part of a first-in-human clinical trial (NCT03449030).

中文翻译：

---

新型抗 GCC 抗体-药物偶联物在患者来源的异种移植物中的临床前抗肿瘤活性和生物分布。

鸟苷酸环化酶 C (GCC) 是一种独特的治疗靶点，其表达仅限于上皮细胞紧密连接的顶端，被认为只能通过静脉内给药的药物在 GCC 表达异常的恶性组织上获得。在本研究中，我们试图评估第二代研究抗体药物偶联物 (ADC) TAK-164 的治疗潜力，该偶联物包含通过肽接头偶联到高细胞毒性 DNA 烷化剂 DGN549 的人抗 GCC mAb . TAK-164 的体外结合、有效载荷释放和体外活性的特征是激发体内评估。在异种移植模型和原发性人类肿瘤异种移植 (PHTX) 模型中评估了 TAK-164 的功效以及与暴露、药效标志物激活和生物分布的关系。我们证明 TAK-164 选择性地结合到表达 GCC 的细胞，并被其内在化，并在体外对表达 GCC 的细胞具有有效的细胞毒作用。单次静脉注射 TAK-164 (0.76 mg/kg) 可显着抑制转移性结直肠癌 PHTX 模型的生长速度。此外，影像学研究表征了 TAK-164 摄取和活性，并显示 GCC 表达和肿瘤摄取之间存在正相关关系，这与抗肿瘤活性相关。总的来说，我们的数据表明 TAK-164 在多种 GCC 阳性肿瘤中具有高度活性，包括那些对 TAK-264（一种 GCC 靶向 auristatin ADC）难治的肿瘤。在表达 GCC 的异种移植物和 PHTX 模型中，89Zr 标记的 TAK-164 的摄取、GCC 表达水平以及最显着的对 TAK-164 治疗的反应之间存在密切关系。