Nakamura Koji, Takahashi Kota, Sakaguchi Izumi, Satoh Takumi, Zhang Lingyi, Yanai Hiroyuki, Tsukumo Yukihito
Chiome Bioscience Inc., 3-12-1 Honmachi, Shibuya-ku, Tokyo 151-0071, Japan.
Int J Mol Sci. 2024 Dec 19;25(24):13627. doi: 10.3390/ijms252413627.
Delta-like 1 homolog (DLK1), a non-canonical Notch ligand, is highly expressed in various malignant tumors, especially in hepatocellular carcinoma (HCC). CBA-1205 is an afucosylated humanized antibody against DLK1 with enhanced antibody-dependent cellular cytotoxicity (ADCC). The binding characteristics of CBA-1205 were analyzed by enzyme-linked immunosorbent assay and fluorescence-activated cell sorting assay. The ADCC activity of CBA-1205 was assessed. The anti-tumor efficacy of CBA-1205 was evaluated in xenograft mouse models, and toxicity and toxicokinetic profiles of CBA-1205 were evaluated in cynomolgus monkeys. CBA-1205 selectively bound to DLK1 among the Notch ligands and only to monkey and human DLK1. The binding epitope was between epidermal growth factor-like domains 1 and 2 of DLK1, which are not involved in any known physiological functions. The ADCC activity of CBA-1205 was confirmed using human peripheral blood mononuclear cells as effector cells. CBA-1205 as a single agent and in combination with lenvatinib demonstrated long-lasting anti-tumor efficacy, including tumor regression, in two liver cancer xenograft models. The toxicity and toxicokinetic profiles of CBA-1205 in cynomolgus monkeys were favorable. These findings suggest that CBA-1205 has the potential to be a useful therapeutic option for drug treatment in HCC. A phase 1 study is ongoing in patients with advanced cancers (jRCT2080225288, NCT06636435).
Delta样1同源物（DLK1）是一种非经典的Notch配体，在各种恶性肿瘤中高表达，尤其是在肝细胞癌（HCC）中。CBA-1205是一种抗DLK1的去岩藻糖基化人源化抗体，具有增强的抗体依赖性细胞毒性（ADCC）。通过酶联免疫吸附测定和荧光激活细胞分选测定分析CBA-1205的结合特性。评估CBA-1205的ADCC活性。在异种移植小鼠模型中评估CBA-1205的抗肿瘤疗效，并在食蟹猴中评估CBA-1205的毒性和毒代动力学特征。CBA-1205在Notch配体中选择性结合DLK1，并且仅结合猴和人DLK1。结合表位位于DLK1的表皮生长因子样结构域1和2之间，这两个结构域不参与任何已知的生理功能。使用人外周血单核细胞作为效应细胞证实了CBA-1205的ADCC活性。在两种肝癌异种移植模型中，CBA-1205作为单一药物以及与乐伐替尼联合使用均显示出持久的抗肿瘤疗效，包括肿瘤消退。CBA-1205在食蟹猴中的毒性和毒代动力学特征良好。这些发现表明，CBA-1205有可能成为HCC药物治疗的有用选择。一项针对晚期癌症患者的1期研究正在进行中（jRCT2080225288，NCT06636435）。
