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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)是一类能同时识别并结合两种抗原或同一抗原的两个不同表位的工程化抗体,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3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,Blinatumomab、Teclistamab和Cadonilimab等代表性药物已实现上市转化。针对bsAbs面临的安全性问题,以及半衰期短、免疫逃逸和实体瘤穿透障碍等挑战,近年来的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、安全的治疗方案。

     

    Abstract: Bispecific antibodies (bsAbs) are a class of engineered antibodies capable of simultaneously recognizing and binding to two distinct antigens or two different epitopes of the same antigen. In recent years, they have demonstrated remarkable therapeutic potential in malignant tumors, autoimmune diseases, and other fields. This review systematically summarizes the developmental trajectory and structural classifications of bsAbs, with a particular focus on three principal mechanisms of action: immune cell redirection, synergistic regulation of signaling pathways, and targeted delivery of effector molecules. The design features and engineering optimization strategies of IgG-like and non-IgG-like formats are also discussed. Clinically, bsAbs have achieved breakthrough progress in hematologic malignancies and are gradually expanding into solid tumors and autoimmune diseases. Representative drugs such as Blinatumomab, Teclistamab, and Cadonilimab have already reached market approval. Addressing the safety concerns of bsAbs, as well as challenges including short half-life, immune evasion, and limited tumor penetration, recent research has focused on strategies such as logic-gated design, prodrug antibodies, mRNA delivery platforms, and trispecific formats to enhance therapeutic selectivity and functional diversity. With continuous advances in antibody engineering, delivery systems, and combination therapies, bsAbs are expected to become a cornerstone of precision immunotherapy, offering more effective and safer treatment options for complex diseases.

     

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