新型抗CTLA-4抗体JS007在晚期实体瘤患者中的临床前研究及首次人体1a期试验。

Preclinical investigations and a first-in-human phase 1a trial of JS007, a novel anti-CTLA-4 antibody, in patients with advanced solid tumors.

作者信息

Zhou Chenfei, Jiang Jinling, Xiang Xiaojun, Liu Hongli, Wu Guowu, Zeng Ruichao, Lu Tong, Zhang Mengqi, Shen Yuteng, Hong Min, Zhang Jun

机构信息

Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.

出版信息

Exp Hematol Oncol. 2024 Oct 1;13(1):98. doi: 10.1186/s40164-024-00567-7.

DOI:10.1186/s40164-024-00567-7

PMID:39354625

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11443874/

Abstract

BACKGROUND

Blocking cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) shows substantial antitumor efficacy. Here, we report the preclinical data and outcomes of a first-in-human phase 1a trial of JS007, a novel anti-CTLA-4 antibody, in advanced solid tumors.

METHODS

In preclinical studies, both in vitro characteristics and in vivo characteristics of JS007 were investigated. The clinical trial included a dose escalation phase and a dose expansion phase. Eligible patients with previously treated advanced solid tumors were enrolled. In the dose escalation phase, JS007 was administered intravenously every 3 weeks at doses of 0.03, 0.3, 1, 3, and 10 mg/kg. Then, 3 and 10 mg/kg were chosen for the dose expansion phase. The primary endpoints included the maximum tolerated dose (MTD) of JS007 based on dose-limiting toxicities (DLTs) and safety.

RESULTS

JS007 could effectively bind to CTLA-4 and induce an immune response in vitro. Potent in vivo antitumor activity of JS007 was observed. Increased T cell infiltration and T regulatory (Treg) cell depletion in tumor microenvironment of cancer cell xenografts were detected after treated with JS007. Pharmacological analysis in experimental animals showed a dose-proportional increase in exposure. In the clinical trial, a total of 28 patients were treated with JS007 across 5 dose levels. No DLTs occurred. The MTD did not reach at the highest dose tested (10 mg/kg). Twenty-three (82.1%) patients experienced at least one treatment-related adverse event (TRAE). The incidence of Grade ≥ 3 TRAEs was 28.6% (8/28) with alanine aminotransferase increase (7.1%, 2/28) being the most frequently reported TRAE. No severe immune-related adverse event (irAE) occurred. Pharmacological profiles of JS007 in patients were similar to those in animal models. Serum concentration of JS007 showed a dose-dependent escalation, and the half-life of JS007 was 9.4 ~ 12.2 days. Treatment-induced anti-drug antibody was detected in 2 patients. The disease control rate was 50% (14/28), and the median overall survival was 14.7 months.

CONCLUSIONS

JS007 preliminarily demonstrates good tolerance and encouraging antitumor activity in patients with previously treated advanced solid tumors.

TRIAL REGISTRATION

ClinicalTrials.gov identifier: NCT05049265 (Sep 20, 2021).

摘要

背景

阻断细胞毒性T淋巴细胞相关抗原4（CTLA-4）显示出显著的抗肿瘤疗效。在此，我们报告了新型抗CTLA-4抗体JS007在晚期实体瘤患者中的首例人体1a期临床试验的临床前数据和结果。

方法

在临床前研究中，对JS007的体外特性和体内特性进行了研究。该临床试验包括剂量递增阶段和剂量扩展阶段。纳入了先前接受过治疗的晚期实体瘤合格患者。在剂量递增阶段，JS007每3周静脉注射一次，剂量分别为0.03、0.3、1、3和10mg/kg。然后，选择3mg/kg和10mg/kg用于剂量扩展阶段。主要终点包括基于剂量限制性毒性（DLT）和安全性的JS007的最大耐受剂量（MTD）。

结果

JS007能有效结合CTLA-4并在体外诱导免疫反应。观察到JS007在体内具有强大的抗肿瘤活性。用JS007治疗后，在癌细胞异种移植瘤的肿瘤微环境中检测到T细胞浸润增加和调节性T（Treg）细胞耗竭。实验动物的药理学分析显示暴露量呈剂量比例增加。在临床试验中，共有28名患者在5个剂量水平接受了JS007治疗。未发生DLT。在测试的最高剂量（10mg/kg）未达到MTD。23名（82.1%）患者经历了至少一次治疗相关不良事件（TRAE）。≥3级TRAE的发生率为28.6%（8/28），谷丙转氨酶升高（7.1%，2/28）是最常报告的TRAE。未发生严重免疫相关不良事件（irAE）。JS007在患者中的药理学特征与动物模型相似。JS007的血清浓度呈剂量依赖性升高，JS007的半衰期为9.4至12.2天。在2名患者中检测到治疗诱导的抗药物抗体。疾病控制率为50%（14/28），中位总生存期为14.7个月。