《生命科学》 2026, 38(7): 1256-1265

LGR5靶点抗体药物的开发及其在肿瘤治疗中的应用 前景

张天豪¹ , 李 涛¹ , 陶维红^1,2,*

¹河南大学抗体药物开发技术国家地方联合工程实验室，开封 475004 ²上海溪长生物技术有限公司，上 海 201712

摘　要：

癌症是全球范围内防治难度极高的疾病之一，LGR5作为Wnt信号通路的关键靶点，在结直肠癌、肝癌等多种恶 性肿瘤中过表达，具备成为治疗靶点的巨大潜力。当前LGR5靶向药物开发面临肿瘤异质性、潜在不良反应等挑战，但 临床前研究显示抗体药物偶联物已展现出显著抗肿瘤活性，为突破难点提供了方向。本文系统综述了LGR5靶点抗体 药物的研发进展，涵盖抗体药物偶联物（ADC）、纳米抗体、双特异性抗体及CAR-T疗法等。ADC药物通过将抗LGR5单 克隆抗体与毒素偶联，在结直肠癌和神经母细胞瘤模型中有效抑制肿瘤生长；纳米抗体凭借小分子量增强肿瘤穿透性， 并抑制Wnt信号通路。文章还探讨了LGR5靶点抗体药物开发的核心难题——在靶/脱靶毒性的机制及解决策略。

通讯作者：陶维红 , Email:taoweihong123@163.com

Development of LGR5-targeted antibody drugs and their prospects in tumor therapy

ZHANG Tian-Hao¹ , LI Tao¹ , TAO Wei-Hong^1,2,*

¹Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng 475004, China ²Shanghai Constreambio Biotechnology Co. , Ltd, Shanghai, 201712, China

Abstract:

Cancer remains one of the most formidable global health challenges, with tumor recurrence and metastasis serving as the primary causes of mortality, largely attributed to the persistence of therapy-resistant cancer stem cells (CSCs). Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), a critical downstream mediator of Wnt/β-catenin signaling pathway, has emerged as a highly promising therapeutic target. This receptor is specifically overexpressed in CSCs and multiple aggressive malignancies including colorectal cancer, hepatocellular carcinoma, and neuroblastoma, while its expression in normal tissues is largely restricted to homeostatic stem cell compartments, offering a favorable therapeutic window. Targeting LGR5 thus offers a strategy to eradicate tumor-initiating cells, which are responsible for disease relapse and treatment failure following conventional chemotherapies. Despite this potential, the development of LGR5-targeted therapeutics has encountered notable obstacles, including tumor heterogeneity and concerns over on-target off-tumor toxicities due to its physiological expression in normal intestinal stem cells. This review systematically summarizes the recent advances in LGR5-targeted antibody-based therapeutics, covering multiple innovative modalities to address these challenges. Antibody-drug conjugates (ADCs), such as the PBD-based SG3199 and camptothecin-conjugated R462-CPT2, have demonstrated potent and selective antitumor efficacy in preclinical models, effectively suppressing tumor growth in both colorectal cancer and neuroblastoma without inducing severe systemic toxicities. Nanobodies targeting LGR5, with their small molecular weight (~15 kDa), enable deep tumor penetration and effectively inhibit aberrant Wnt signaling, showing significant anti-proliferative effects in both in vitro cell assays and in vivo animal models. Furthermore, bispecific antibodies (e.g., petosemtamab) and LGR5-targeted CAR-T cell therapies have advanced into clinical trials, providing new avenues to overcome treatment resistance and prevent tumor recurrence. Collectively, these emerging strategies hold great promise for eradicating CSCs and improving clinical outcomes for hard-to-treat cancers, paving the way for next-generation targeted cancer therapies.

Communication Author：TAO Wei-Hong , Email:taoweihong123@163.com