PO.CL05.11 · 临床研究
DXP-106：一款具有增强ADCC活性的抗IL1RAP单克隆抗体，展现出体外和体内抗肿瘤效应并已成功完成IND申报支持研究
DXP-106, an anti-IL1RAP monoclonal antibody with enhanced ADCC activity, exhibits both in vitro and in vivo anti-tumor effects and has successfully completed IND-enabling studies
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摘要 Abstract
中文摘要
背景：白细胞介素-1受体辅助蛋白（IL1RAP）在多种癌症类型的肿瘤微环境（TME）内表达于癌细胞、基质细胞和浸润性免疫细胞上。通过激活IL-1超家族信号通路，IL1RAP在多个阶段促进肿瘤进展，使其成为一个有前景的癌症治疗靶点。
方法：使用冷冻电镜（Cryo-EM）鉴定了DXP-106的表位。通过一系列利用报告细胞系、原代HUVEC细胞和A431人鳞状细胞癌模型的实验评估了该抗体对IL-1、IL-33和IL-36信号的抑制活性。使用细胞系来源异种移植（CDX）模型评估了体内疗效。DXP-106治疗产品采用FUT8敲除的中国仓鼠卵巢（CHO）细胞系生产，以增强抗体依赖性细胞介导的细胞毒性（ADCC）活性。
结果：基于Cryo-EM的表位定位揭示DXP-106结合于IL1RAP结构域2内的一个独特位点，该区域与IL1beta-IL1R1和IL1RAP的关键界面重叠。体外研究表明DXP-106有效阻断了全部六条IL-1家族通路的信号：IL-1alpha、IL-1beta、IL-33以及IL-36alpha、IL-36beta、IL-36gamma。此外，DXP-106在肿瘤细胞杀伤实验中表现出强劲的ADCC活性，并在异种移植模型中显著抑制肿瘤生长。已成功建立稳健且高产的生产工艺，产出临床可用产品。非临床安全性评估，包括在非人灵长类动物中开展的符合GLP的毒性研究，未显示显著不良发现。
结论：DXP-106是一款强效单克隆抗体，特异性结合IL1RAP上的独特表位，广泛抑制全部六条IL-1家族信号通路，并在体外和体内均显示出强劲的抗肿瘤活性。IND申报支持研究已成功完成，首次人体（FIH）临床试验计划于2026年第一季度开展。
查看英文原文 English abstract
Background: The Interleukin-1 Receptor Accessory Protein (IL1RAP) is expressed on cancer cells, stromal cells, and infiltrating immune cells within the tumor microenvironment (TME) across various cancer types. By activating the IL-1 superfamily signaling pathways, IL1RAP contributes to tumor progression at multiple stages, making it a promising therapeutic target for cancer treatment.
Methods: The epitope of DXP-106 was identified using cryo-electron microscopy (Cryo-EM). The antibody's inhibitory activity against IL-1, IL-33, and IL-36 signaling was assessed through a range of assays utilizing reporter cell lines, primary HUVEC cells, and the A431 human squamous cell carcinoma model. In vivo efficacy was evaluated using a cell line-derived xenograft (CDX) model. The DXP-106 therapeutic product was manufactured using FUT8 knockout Chinese hamster ovary (CHO) cell lines to enhance the antibody-dependent cellular cytotoxicity (ADCC) activity.
Results: Cryo-EM-based epitope mapping revealed that DXP-106 binds to a unique site within IL1RAP domain 2, an area that overlaps with the key interfaces of IL1beta-IL1R1 and IL1RAP. In vitro studies demonstrated that DXP-106 effectively blocked signaling through all six IL-1 family pathways: IL-1alpha, IL-1beta, IL-33, and IL-36alpha, IL-36beta, IL-36gamma. Additionally, DXP-106 exhibited strong ADCC activity in tumor cell killing assays and significantly suppressed tumor growth in xenograft models. A robust and high-yield manufacturing process has been successfully established, yielding clinical-ready product. Nonclinical safety evaluations, including GLP-compliant toxicity studies in non-human primates, showed no significant adverse findings.
Conclusions: DXP-106 is a potent monoclonal antibody that specifically binds to a unique epitope on IL1RAP, broadly inhibits all six IL-1 family signaling pathways, and shows robust anti-tumor activity both in vitro and in vivo. IND-enabling studies have been successfully completed, and the first-in-human (FIH) clinical trial is planned for the first quarter of 2026.
利益披露 Disclosure
Q. Liu, None..
Y. Ru, None..
Y. Jiang, None..
H. Li, None..
W. Li, None..
L. Yang, None..
Q. Shi, None.