CStone Pharmaceuticals (Suzhou) Co., Ltd, Shanghai, 201203, China.
Wuxi Biologics Co. Ltd, Wuxi, 214092, China.
Acta Pharmacol Sin. 2021 Jan;42(1):142-148. doi: 10.1038/s41401-020-0422-6. Epub 2020 May 28.
The programmed cell death protein 1 (PD-1) is an immune-checkpoint that negatively regulates the immune system and a key mechanism that tumors utilize to escape from immune surveillance. PD-1 antibodies can block the interaction of PD-1 with its ligands (PD-L1 and PD-L2), restore T cells activation, and elicit antitumor activity. In this paper, we reported a novel PD-1 monoclonal antibody (mAb) CS1003, which is a humanized IgG4 PD-1 mAb generated by conventional hybridoma technology, and currently being developed in multiple clinical trials as monotherapy or in combination with other anticancer agents. We showed that CS1003 bound to recombinant human, cynomolgus monkey, and mouse PD-1 with EC values of 0.1757, 0.2459, and 0.3664 nM, respectively. CS1003 blocked PD-1 interaction with its ligands, dose-dependently enhanced T cell proliferation and secretion of cytokines (IL-2 and IFN-γ) to the levels comparable to the reference antibody pembrolizumab. Intraperitoneal administration of CS1003 (0.1, 0.5, 2.5 mg/kg, once every 3 days) dose-dependently suppressed the growth of MC38-hPD-L1 colon cancer in hPD-1 knock-in mice. Pharmacokinetics (PK) study revealed a linear PK profile within the dose range of 2-18 mg/kg following single intravenous administration in cynomolgus monkey. These data provide a comprehensive preclinical characterization of CS1003 that supports its clinical development for cancer immunotherapy.
程序性细胞死亡蛋白 1（PD-1）是一种免疫检查点，可负向调节免疫系统，是肿瘤逃避免疫监视的关键机制。PD-1 抗体可阻断 PD-1 与其配体（PD-L1 和 PD-L2）的相互作用，恢复 T 细胞的激活，并引发抗肿瘤活性。在本文中，我们报道了一种新型 PD-1 单克隆抗体（mAb）CS1003，它是一种通过常规杂交瘤技术产生的人源化 IgG4 PD-1 mAb，目前正在多项临床试验中作为单药或与其他抗癌药物联合开发。我们表明 CS1003 与人、食蟹猴和小鼠的重组 PD-1 结合的 EC 值分别为 0.1757、0.2459 和 0.3664 nM。CS1003 阻断 PD-1 与其配体的相互作用，剂量依赖性地增强 T 细胞增殖和细胞因子（IL-2 和 IFN-γ）的分泌，达到与参比抗体 pembrolizumab 相当的水平。CS1003（0.1、0.5、2.5 mg/kg，每 3 天腹腔注射一次）剂量依赖性地抑制了 hPD-1 敲入小鼠中 MC38-hPD-L1 结肠癌的生长。在食蟹猴中单次静脉注射 2-18 mg/kg 范围内，药代动力学（PK）研究显示 PK 呈线性特征。这些数据为 CS1003 的全面临床前特征提供了支持，为其癌症免疫治疗的临床开发提供了依据。
