RemeGen, Ltd., Yantai 264006, Shandong, China.
Mabplex International Ltd., Yantai 264006, Shandong, China.
Int Immunopharmacol. 2018 Sep;62:299-308. doi: 10.1016/j.intimp.2018.06.034. Epub 2018 Jul 23.
B-cell lymphoma remains one of the most refractory tumors, and as such the development of novel treatment approaches, such as antibody-drug conjugates (ADCs), is required. To improve the stability and homogeneity of the ADCs, a humanized anti-CD19 monoclonal antibody (RC58) was developed in the present study. RC58 was based on the CD19 antigen as a potential molecular target of human B-cell lymphomas. RC58 has high CD19-binding affinity and can be internalized in CD19-positive cells through endocytosis. Furthermore, three types of RC58-based ADCs (ADC-1, ADC-2, and ADC-3) were generated using three kinds of Maleimide-PEG-based linkers with two different cytotoxins. The anti-tumor activities of the ADCs were confirmed by in vitro and in vivo experiments. The stability of the ADCs was also evaluated by incubation in human plasma for 10 days. In vitro experiments showed that the three ADCs had distinct inhibitory effects on several B-lymphoma cell lines. Meanwhile, a close correlation between efficacy and drug concentration was found in a nude mouse xenograft model of human B-cell lymphoma, after treatment with RC58-based ADCs. Our results suggest that ADC-1, with high efficiency, could be used as a potential therapeutic agent for human B-cell malignancies.
B 细胞淋巴瘤仍然是最难治愈的肿瘤之一，因此需要开发新的治疗方法，如抗体药物偶联物（ADC）。为了提高 ADC 的稳定性和均一性，本研究开发了一种人源化抗 CD19 单克隆抗体（RC58）。RC58 基于 CD19 抗原，作为人类 B 细胞淋巴瘤的潜在分子靶标。RC58 对 CD19 具有高结合亲和力，并可通过内吞作用在 CD19 阳性细胞中内化。此外，使用三种基于马来酰亚胺-PEG 的连接子和两种不同的细胞毒素生成了三种基于 RC58 的 ADC（ADC-1、ADC-2 和 ADC-3）。通过体外和体内实验证实了 ADC 的抗肿瘤活性。通过在人血浆中孵育 10 天评估 ADC 的稳定性。体外实验表明，三种 ADC 对几种 B 淋巴瘤细胞系具有明显的抑制作用。同时，在人 B 细胞淋巴瘤裸鼠异种移植模型中，在用 RC58 基 ADC 治疗后，发现疗效与药物浓度之间存在密切相关性。我们的结果表明，具有高效的 ADC-1 可用作人类 B 细胞恶性肿瘤的潜在治疗剂。
