肿瘤细胞治疗研究
英文原题：Next-generation antibody-based therapeutics in cancer: antibody-drug conjugates bispecific antibodies across hematologic malignancies and solid tumors.
肿瘤学的治疗范式正在经历由抗体药物偶联物（ADC）和双特异性抗体（bsAb）驱动的深刻变革。
肿瘤学的治疗范式正在抗体-药物偶联物（ADC）和双特异性抗体（bsAb）的推动下经历深刻变革。本综述全面总结了这些平台在血液系统恶性肿瘤和实体瘤中的近期临床进展。以 trastuzumab deruxtecan 为代表的 ADC 拓展了可靶向 HER2 表达的概念，展现出有意义的颅内活性，并重新定义了 HER2 低表达乳腺癌及其他领域的治疗标准。随着新型 ADC 靶点（TROP2、CLDN18.2、B7-H3、HER3）和双特异性 ADC 构建体的出现，这一领域持续扩展。与此同时，T 细胞衔接型 bsAb——B 细胞淋巴瘤中的 CD20×CD3、多发性骨髓瘤中的 BCMA×CD3 和 GPRC5D×CD3，以及急性淋巴细胞白血病中的 CD19×CD3——在重度经治人群中实现了深度且持久的缓解。在实体瘤中，靶向 EGFR-MET 和 DLL3 的 bsAb 在历史上难以治疗的场景中提供了经临床验证的疗效，包括 tarlatamab 获得监管批准。尽管取得了这些成功，关键挑战依然存在，包括独特毒性特征的管理、通过抗原逃逸和 T 细胞耗竭出现的耐药，以及缺乏经过验证的预测性生物标志物。这些药物彼此之间以及与CAR-T 细胞治疗的最佳序贯方案在很大程度上仍属经验性。下一代策略——双特异性 ADC、前体药物偶联物和免疫刺激性抗体偶联物——与免疫治疗联合方案有望克服耐药并改善治疗指数。通过提炼关键临床数据并突出未解决的问题，本综述为将基于抗体的创新转化为精准肿瘤学提供了路线图。
The therapeutic paradigm in oncology is undergoing a profound transformation driven by antibody-drug conjugates (ADCs) and bispecific antibodies (bsAbs). This review comprehensively summarizes recent clinical advances of these platforms across both hematologic malignancies and solid tumors. ADCs such as trastuzumab deruxtecan have expanded the concept of targetable HER2 expression, demonstrating meaningful intracranial activity and redefining standards of care in HER2-low breast cancer and beyond. The landscape continues to broaden with novel ADC targets (TROP2, CLDN18.2, B7-H3, HER3) and bispecific ADC constructs. Concurrently, T‑cell-engaging bsAbs-CD20×CD3 in B‑cell lymphomas, BCMA×CD3 and GPRC5D×CD3 in multiple myeloma, and CD19×CD3 in acute lymphoblastic leukemia-have achieved deep and durable responses in heavily pretreated populations. In solid tumors, EGFR‑MET and DLL3‑targeted bsAbs have delivered clinically validated efficacy in historically refractory settings, including regulatory approval of tarlatamab. Despite these successes, critical challenges persist, including the management of unique toxicity profiles, the emergence of resistance via antigen escape and T‑cell exhaustion, and the absence of validated predictive biomarkers. Optimal sequencing of these agents with one another and with chimeric antigen receptor T‑cell therapy remains largely empirical. Next‑generation strategies-bispecific ADCs, probody‑drug conjugates, and immune‑stimulating antibody conjugates-combined with immunotherapy partnerships hold promise for overcoming resistance and improving therapeutic indices. By distilling pivotal clinical data and highlighting unresolved questions, this review provides a roadmap for translating antibody‑based innovations into precision oncology.
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