| 樊霖洁,王 洁,王志杰.实体瘤抗体药物偶联物生物标志物及耐药机制研究进展[J].肿瘤学杂志,2025,31(7):567-577. |
| 实体瘤抗体药物偶联物生物标志物及耐药机制研究进展 |
| Advances on the Biomarkers and Mechanisms of Resistance to Antibody-Drug Conjugate in Solid Tumors |
| 投稿时间：2024-11-11 |
| DOI：10.11735/j.issn.1671-170X.2025.07.B002 |
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| 中文关键词: 抗体药物偶联物 生物标志物 耐药机制 联合治疗 |
| 英文关键词:antibody-drug conjugate biomarker resistance mechanism combination therapies |
| 基金项目:国家重点研发计划（2022YFC2505000）；2022年黑龙江省“揭榜挂帅”科技攻关项目（2022ZXJ03C0） |
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| 中文摘要: |
| 摘 要：抗体药物偶联物（antibody-drug conjugate，ADC）通过单克隆抗体的特异性靶向作用实现细胞毒性药物载荷的精准递送，近年来在多种难治性恶性肿瘤，如三阴性乳腺癌、小细胞肺癌和尿路上皮癌等治疗领域展现出临床价值。然而，ADC在不同患者中的疗效仍有明显差异，亟待明确其治疗优势人群。目前ADC生物标志物研究主要聚焦于靶抗原表达水平，对其他潜在预测指标如肿瘤基因组特征、内吞相关蛋白、药物转运体活性及肿瘤微环境免疫特征等方面的系统性研究仍显不足。ADC耐药问题不可避免，其机制涉及多个关键作用环节的功能障碍，包括靶抗原介导的内化效率降低、溶酶体降解异常、有效载荷耐药以及免疫调节功能失调等。针对上述挑战，当前研究提出了开发基于ADC的联合治疗方案、设计新型ADC药物以及优化给药方案三大克服耐药策略。全文系统综述了ADC药物生物标志物研究进展、耐药机制的最新认识以及克服耐药的应对策略，为后续基础研究及临床转化研究提供理论依据和实践指导。 |
| 英文摘要: |
| Abstract： Antibody-drug conjugate(ADC) achieve precise delivery of cytotoxic payloads through the specific targeting of monoclonal antibodies，demonstrating significant clinical value in recent years for treating various refractory malignancies such as triple-negative breast cancer，small cell lung cancer，and urothelial carcinoma. However，ADC efficacy varies considerably among patients，necessitating the identification of optimal beneficiary populations. Current biomarker research primarily focuses on target antigen expression levels，while systematic investigations into other potential predictive indicators，including tumor genomic profiles，endocytosis-related proteins，drug transporter activity，and tumor microenvironment immune characteristics，remain inadequate. Furthermore，ADC resistance is inevitable，with underlying mechanisms involving dysfunction across multiple critical processes，including reduced target antigen-mediated internalization efficiency，aberrant lysosomal degradation，payload resistance，and immune regulatory dysfunction. To address these challenges，current research has proposed three major resistance-overcoming strategies：developing ADC-based combination therapies，designing novel ADC constructs，and optimizing dosing regimens. This paper systematically summarizes recent advances in ADC biomarker research，current understanding of resistance mechanisms，and corresponding strategies to overcome resistance，thereby providing insights for future basic and translational clinical investigations. |
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