HBM4003 是一种新型抗 CTLA-4 重链抗体，旨在增强 Treg 消融和抗体依赖性细胞介导的细胞毒性，同时确保可控的安全性。该I期试验研究了HBM4003联合抗PD-1抗体特瑞普利单抗治疗晚期实体瘤患者的安全性、药代动力学、免疫原性和初步疗效，特别是针对黑色素瘤。这项多中心、开放标签的I期试验分为两个阶段部分：剂量递增阶段（第 1 部分）和剂量扩展阶段（第 2 部分）。第1部分中，HBM4003以0.03、0.1、0.3mg/kg的剂量与特瑞普利单抗联合给药，固定剂量为每3周240mg。扩展阶段使用推荐的 II 期剂量（RP2D）。主要终点是第 1 部分的安全性和 RP2D，第 2 部分的客观缓解率 (ORR)。探索了基于细胞因子和多重免疫荧光染色的生物标志物。总共 40 名患者接受了研究治疗，其中 36 名患者接受 HBM4003 0.3mg 的 RP2D 治疗。 /kg 每 3 周加特瑞普利单抗 240 mg。 36 名参与者 (90.0%) 经历了至少一种治疗相关不良事件 (TRAE)，其中 10 名 (25.0%) 名患者经历了 ≥3 级 TRAE，5 名 (12.5%) 名患者经历了最严重的免疫介导不良事件 (irAE) 3 级。未发生 4 级或 5 级 irAE。疗效分析集包括 32 名接受 RP2D 治疗的黑色素瘤患者，并具有可用的基线后成像数据。抗PD-1/PD-L1治疗初治亚组和抗PD-1/PD-L1治疗失败亚组的ORR分别为33.3%和5.9%。在粘膜黑色素瘤中，两个亚组的 ORR 分别为 40.0% 和 10.0%。肿瘤中的基线高 Treg/CD4 比率是免疫治疗疗效的独立预测因素。HBM4003 0.3mg/kg 加每 3 周 240mg 特瑞普利单抗在实体瘤中显示出可控的安全性，并且没有新的安全信号。有限的数据表明其具有良好的抗肿瘤活性，尤其是在未经 PD-1 治疗的粘膜黑色素瘤中。NCT04727164.© 作者（或其雇主）2024。根据 CC BY-NC 允许重复使用。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

HBM4003 is a novel anti-CTLA-4 heavy chain-only antibody, designed to enhance Treg ablation and antibody-dependent cell-mediated cytotoxicity while ensuring a manageable safety profile. This phase I trial investigated the safety, pharmacokinetics, immunogenicity and preliminary efficacy of HBM4003 plus with anti-PD-1 antibody toripalimab in patients with advanced solid tumors, especially focusing on melanoma.The multicenter, open-label phase I trial was divided into two parts: dose-escalation phase (part 1) and dose-expansion phase (part 2). In part 1, HBM4003 was administered at doses of 0.03, 0.1, 0.3 mg/kg in combination with toripalimab with fixed dosage of 240 mg every 3 weeks. The recommended phase II dose (RP2D) was used in the expansion phase. Primary endpoints were safety and RP2D in part 1 and objective response rate (ORR) in part 2. Biomarkers based on cytokines and multiplex immunofluorescence staining were explored.A total of 40 patients received study treatment, including 36 patients treated with RP2D of HBM4003 0.3 mg/kg plus toripalimab 240 mg every 3 week. 36 participants (90.0%) experienced at least one treatment-related adverse event (TRAE), of which 10 (25.0%) patients experienced grade ≥3 TRAEs and 5 (12.5%) experienced immune-mediated adverse events (irAEs) with maximum severity of grade 3. No grade 4 or 5 irAEs occurred. Efficacy analysis set included 32 melanoma patients treated with RP2D and with available post-baseline imaging data. The ORRs of anti-PD-1/PD-L1 treatment-naïve subgroup and anti-PD-1/PD-L1 treatment-failed subgroup were 33.3% and 5.9%, respectively. In mucosal melanoma, the ORR of the two subgroups were 40.0% and 10.0%, respectively. Baseline high Treg/CD4+ratio in the tumor serves as an independent predictive factor for the efficacy of immunotherapy.HBM4003 0.3 mg/kg plus toripalimab 240 mg every 3 week demonstrated manageable safety in solid tumors and no new safety signal. Limited data demonstrated promising antitumor activity, especially in PD-1 treatment-naïve mucosal melanoma.NCT04727164.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.