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双特异性抗体的研究进展与临床应用

Research Progress and Clinical Applications of Bispecific Antibodies

  • 摘要: 双特异性抗体(bispecific antibodies,bsAbs)是一类可同时识别两个不同抗原表位的工程抗体,近年来在恶性肿瘤、自身免疫疾病等领域展现出显著的治疗潜力。本综述系统梳理了bsAbs的发展历程与结构分类,重点分析了其三种主要作用机制:免疫细胞重定向、信号通路协同调控和靶向效应分子递送,并总结了IgG样与非IgG样构型的设计特点与工程优化策略。在临床方面,bsAbs在血液系统恶性肿瘤中已取得突破性进展,并逐步向实体瘤及自身免疫疾病拓展,代表性药物如Blinatumomab、Teclistamab和Cadonilimab等已实现上市转化。针对bsAbs面临的安全性、半衰期短、免疫逃逸和实体瘤穿透障碍等挑战,近年来研究聚焦于逻辑门控设计、前体抗体、mRNA递送平台及三特异结构等方向,以提升其治疗选择性和功能多样性。随着抗体工程、递送系统和联合治疗策略的不断进步,bsAbs有望成为精准免疫治疗的重要支柱,为复杂疾病提供更高效、更安全的治疗方案。

     

    Abstract: Bispecific antibodies (bsAbs) are a class of engineered antibodies capable of simultaneously recognizing two distinct antigenic epitopes. In recent years, they have demonstrated significant therapeutic potential in the treatment of malignant tumors, autoimmune diseases, and other conditions. This review provides a comprehensive overview of the development and structural classification of bsAbs, with a focus on three primary mechanisms of action: immune cell redirection, synergistic modulation of signaling pathways, and targeted delivery of effector molecules. The structural features and engineering strategies of both IgG-like and non-IgG-like formats are summarized. Clinically, bsAbs have achieved notable breakthroughs in hematologic malignancies and are being increasingly applied to solid tumors and autoimmune disorders. Representative drugs such as Blinatumomab, Teclistamab, and Cadonilimab have already gained regulatory approval. To overcome challenges such as safety concerns, short half-life, immune evasion, and poor tumor penetration, recent studies have focused on logic-gated designs, antibody prodrugs, mRNA delivery platforms, and trispecific constructs to enhance therapeutic selectivity and functional diversity. With continuous advances in antibody engineering, delivery technologies, and combination treatment strategies, bsAbs are poised to become a cornerstone of precision immunotherapy, offering safer and more effective solutions for complex diseases.

     

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