抗体药物偶联物在乳腺癌领域的研究现状与展望

doi:10.19401/j.cnki.1007-3639.2025.02.002

摘要/Abstract

摘要：

抗体药物偶联物（antibody-drug conjugate，ADC）作为乳腺癌精准治疗的突破性药物，其独特的靶向递送机制能够有效地提高抗肿瘤治疗的选择性，并降低传统化疗的非特异性毒性。近年来，ADC在乳腺癌治疗中的应用范围不断拓展，尤其是在人表皮生长因子受体2（human epidermal growth factor receptor 2，HER2）阳性及HER2低表达乳腺癌中的成功应用，显著改变了疾病的治疗格局。其中，恩美曲妥珠单抗（trastuzumab emtansine，T-DM1）是首个取代拉帕替尼+卡培他滨方案，成为HER2阳性乳腺癌二线治疗的ADC类药，而德曲妥珠单抗（trastuzumab deruxtecan，DS-8201，T-DXd）在DESTINY-Breast04研究中展现出对HER2低表达乳腺癌的显著疗效，并成为首个获批用于该亚型患者的ADC。针对滋养层细胞表面抗原2（trophoblast cell surface antigen 2，Trop-2）靶点的ADC如戈沙妥珠单抗（sacituzumab govitecan，SG）也已在三阴性乳腺癌（triple-negative advanced breast cancer，TNBC）及激素受体阳性/HER2阴性乳腺癌患者中展现出良好的临床获益。此外，新一代ADC技术的优化，如提高连接子稳定性、优化药物抗体比（drug-to-antibody ratio，DAR）及增强旁观者效应，进一步提升了药物的抗肿瘤活性及安全性，使其成为乳腺癌精准治疗的重要发展方向。虽然ADC药物在提高疗效的同时仍可能伴随一定的靶点相关及载荷相关的不良反应，但随着管理策略的不断优化，其安全性已得到有效提升。HER2靶向ADC的不良反应主要包括T-DXd相关的间质性肺病（interstitial lung disease，ILD）、T-DM1的血小板减少及肝功能异常，而Trop-2靶向ADC如SG的血液毒性及胃肠道反应亦需关注。值得注意的是，新一代ADC在结构优化后已显著改善其安全性，并且通过早期监测、个体化剂量调整及支持治疗，可以有效地降低严重不良事件的发生风险。临床上ADC治疗的毒性管理已趋向成熟，绝大多数不良反应均可通过优化治疗方案和联合支持治疗得到有效控制。因此，在实际临床操作中，应综合考虑患者的个体因素、既往治疗史及伴随疾病情况，以制定最优的ADC应用策略，确保疗效与安全性的最大化。随着ADC技术的不断进步，未来乳腺癌治疗将更加精准化。新型HER2-Trop-2双靶点ADC的研发为HER2低表达及HER2阴性乳腺癌患者提供了新的治疗可能，而T-DXd联合免疫检查点抑制剂（immune checkpoint inhibitor，ICI）、CDK4/6抑制剂及多腺苷二磷酸核糖聚合酶[poly（ADP-ribose）polymerase，PARP]抑制剂的研究显示出协同抗肿瘤效应。本综述系统总结乳腺癌ADC的最新研究进展，重点探讨HER2及Trop-2靶向ADC的临床应用、安全性管理策略及新型ADC的发展趋势，旨在为乳腺癌的精准治疗提供参考。

关键词: 抗体药物偶联物, 乳腺癌, 靶向治疗, 人表皮生长因子受体2, Trop-2

Abstract:

Antibody-drug conjugates (ADCs) represent a breakthrough in precision therapy for breast cancer, offering a unique targeted drug delivery mechanism that enhances tumor selectivity while reducing the nonspecific toxicity associated with conventional chemotherapy. In recent years, the clinical applications of ADCs in breast cancer have expanded significantly, particularly in human epidermal growth factor receptor 2 (HER2)-positive and HER2-low breast cancer, reshaping the therapeutic landscape. Trastuzumab emtanserin (T-DM1) was the first ADC drug to replace lapatinib plus capecitabine as a second-line treatment for HER2-positive breast cancer, while trastuzumab deruxtecan (T-DXd) demonstrated remarkable efficacy in HER2-low breast cancer in the DESTINY-Breast04 trial, becoming the first approved ADC for this patient subgroup. Furthermore, trophoblast cell surface antigen 2 (Trop-2)-targeting ADCs, such as sacituzumab govitecan (SG), have shown promising clinical benefits in patients with triple-negative breast cancer (TNBC) and hormone receptor-positive/HER2-negative breast cancer. Advances in next-generation ADC technologies, including improvements in linker stability, drug-to-antibody ratio (DAR) optimization, and enhanced bystander effects, have further improved the therapeutic efficacy and safety profile of these agents, reinforcing their role in the precision treatment of breast cancer. Although ADCs have demonstrated substantial clinical benefits, they are associated with target- and payload-related toxicities. However, with ongoing advancements in management strategies, their safety profile has been significantly improved. HER2-targeting ADCs present specific adverse events, including interstitial lung disease (ILD) associated with T-DXd, thrombocytopenia, and liver function abnormalities observed with T-DM1, while Trop-2-targeting ADCs such as SG are linked to hematologic toxicity and gastrointestinal side effects. Notably, structural optimizations in next-generation ADCs have led to significant improvements in their safety profile. Early monitoring, individualized dose modifications, and supportive care measures have been shown to effectively reduce the incidence of severe adverse events. Clinical studies indicate that toxicity management strategies for ADCs have matured, with most adverse effects being effectively controlled through optimized treatment regimens and adjunctive supportive care. Thus, in clinical practice, it is essential to consider patient-specific factors, prior treatment history, and comorbidities to devise an optimal ADC treatment strategy that maximizes both efficacy and safety. As ADC technology continues to evolve, breast cancer treatment is expected to become increasingly precise. The development of novel HER2-Trop-2 bispecific ADCs offers new therapeutic options for patients with HER2-low and HER2-negative breast cancer. Additionally, studies investigating the combination of T-DXd with immune checkpoint inhibitors (ICIs), CDK4/6 inhibitors, and poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated synergistic antitumor effects, further expanding the prospects for precision medicine in breast cancer. This review systematically summarized the latest advancements in ADCs for breast cancer, with a focus on the clinical applications, safety management strategies, and future development of HER2- and Trop-2-targeting ADCs, aiming to provide valuable insights for the future of precision breast cancer treatment.

Key words: Antibody-drug conjugate, Breast cancer, Targeted therapy, Human epidermal growth factor receptor-2, Trop-2

中图分类号:

R737.9

林佳琳, 王文娜, 徐兵河. 抗体药物偶联物在乳腺癌领域的研究现状与展望[J]. 中国癌症杂志, 2025, 35(2): 154-166.

LIN Jialin, WANG Wenna, XU Binghe. Current status and future perspectives of antibody-drug conjugates in breast cancer therapy[J]. China Oncology, 2025, 35(2): 154-166.

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