PO.ET01.06 · 实验与分子治疗
XYD-8006：一种新型ADAM9靶向双载荷ADC在胃肠道和肺癌模型中表现出优越的临床前疗效
XYD-8006: A novel ADAM9-targeting dual-payload ADC demonstrates superior preclinical efficacy in gastrointestinal and lung cancer models
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摘要 Abstract
中文摘要
背景：解整合素金属蛋白酶9（ADAM9）是一种细胞表面蛋白酶，参与生长因子脱落、整合素结合和细胞迁移，这些过程对肿瘤进展、转移和新生血管形成至关重要。其过表达与多种实体瘤的不良预后相关，在胃肠道和肺癌中过表达而在正常组织中有限，凸显了其作为治疗靶点的潜力。虽然抗体偶联药物（ADC）代表了一种变革性的肿瘤治疗模式，但单载荷ADC面临诸多局限，包括肿瘤异质性、DXD/SN38等载荷耐药的出现。为解决这一问题，我们开发了XYD-8006，一种配备双载荷平台的ADAM9靶向ADC，旨在增强疗效并克服肿瘤异质性和DXD/SN38耐药。
方法：XYD-8006为一种人源化抗ADAM9 IgG1单克隆抗体，通过高亲水性连接子偶联两种不同的强效载荷：一种微管抑制剂和一种拓扑异构酶I抑制剂，具有受控且特定的药物抗体比（DAR）。在一组ADAM9高、中、低表达的肿瘤模型中评估该分子的特异性、内化效率及体外/体内疗效。
结果：XYD-8006对ADAM9表现出高特异性，未观察到与同源家族成员的交叉反应性，并表现出优越的内化效率。体外和体内研究显示，XYD-8006诱导强效、协同的肿瘤细胞杀伤，显著优于单载荷ADC对照。值得注意的是，它不仅在ADAM9高表达模型中实现了强效的肿瘤生长抑制和消退，在ADAM9中、低表达模型中也是如此。XYD-8006表现出强效的ADAM9靶向细胞毒性和肿瘤抑制作用，并具有良好的药代动力学和安全性特征。
结论：XYD-8006旨在克服当前ADC治疗的关键局限。其在胃肠道和肺癌中良好的临床前疗效支持其进一步开发，预计将于2026年进入临床研究。
查看英文原文 English abstract
Background: A Disintegrin And Metalloproteinase 9 (ADAM9) is a cell surface protease implicated in growth factor shedding, integrin binding, and cell migration, processes critical for tumor progression, metastasis, and neovascularization. Its overexpression is correlated with poor prognosis in multiple solid tumors, and overexpressed in GI and lung cancers but limited in normal tissues, highlighting its potential as a therapeutic target. While Antibody-Drug Conjugates (ADCs) represent a transformative oncology modality, single-payload ADCs face limitations including, tumor heterogenecity, the emergence of payload resistance such as DXD/SN38. To address this, we developed XYD-8006, a ADAM9-targeting ADC equipped with dual-payload platform designed to enhance efficacy and overcome tumor heterogenecity and DXD/SN38 resistance.
Methods: XYD-8006, a humanized anti-ADAM9 IgG1 monoclonal antibody conjugated with high hydrophilic linker to two distinct potent payloads: a microtubule inhibitor and a topoisomerase I inhibitor, with a controlled and specific Drug-to-Antibody Ratio (DAR). The molecule was evaluated for specificity, internalization efficiency, and in vitro/in vivo efficacy across a panel of ADAM9-high, -medium, and -low expressing tumor models.
Results: XYD-8006 exhibited high specificity for ADAM9 with no observed cross-reactivity to paralog family members and demonstrated superior internalization efficiency. In vitro and in vivo study showed, XYD-8006 induced potent, synergistic tumor cell killing, significantly outperforming single-payload ADC controls. Notably, it achieved robust tumor growth inhibition and regression not only in ADAM9-high models but also in models with medium and low ADAM9 expression. XYD-8006 exhibited potent ADAM9-targeted cytotoxicity and tumor suppression, with a favorable pharmacokinetic and safety profile.
Conclusion: XYD-8006 was designed to overcome key limitations of current ADC therapies. Its promising preclinical efficacy across gastrointestinal and lung cancers supports its further development, with an expected entry into clinical study in 2026.
利益披露 Disclosure
W. Ho, None..
P. Rong, None..
M. Zhao, None..
J. Li, None..
X. Zhang, None..
H. Ding, None..
F. Ouyang, None.