Cruz Víctor L, Duro-Sánchez Jorge, Franco-Mateos Emma, García-Estévez Laura, Pérez-García José, Gion María, Garrigós Laia, Cortez Patricia, Saavedra Cristina, Gómez Patricia, Ortiz Carolina, Aguinagalde Arantxa, Ramos Javier, Cortés Javier, Vega Juan F
BIOPHYM, Departamento de Física Macromolecular, Instituto de Estructura de la Materia, IEM-CSIC, Madrid, Spain.
Breast Cancer Department, MD Anderson Cancer Center, Madrid, Spain.
Sci Rep. 2025 Aug 6;15(1):28715. doi: 10.1038/s41598-025-13810-w.
Antibody-Drug Conjugates (ADCs) are a promising cancer treatment that deliver toxic drugs directly to cancer cells, reducing harm to healthy tissue. A key feature of newer ADCs is the "bystander effect," in which nearby cancer cells are also affected by passive diffusion. However, the mechanisms underlying this effect remain unclear. Using computer simulations, this study investigates how the drug's ionization state and the linker connecting it to the antibody influence its ability to cross cell membranes. The results show that the ionization state of the drug impacts its membrane permeability, as charged molecules encounter resistance when moving through the membrane's hydrophobic core. Moreover, the study reveals that the linker increases the drug's overall size and hydrophobicity, thereby hindering its diffusion to adjacent cells. This finding suggests that linker design can significantly influence the efficacy of antibody-drug conjugates (ADCs) by limiting their ability to reach neighboring cancer cells. These insights enhance our understanding of ADC mechanisms and provide a valuable foundation for the optimization of next-generation ADC therapies targeting breast cancer.
抗体药物偶联物（ADCs）是一种很有前景的癌症治疗方法，它能将有毒药物直接输送到癌细胞，减少对健康组织的损害。新型ADC的一个关键特性是“旁观者效应”，即附近的癌细胞也会受到被动扩散的影响。然而，这种效应背后的机制仍不清楚。本研究利用计算机模拟，探究了药物的电离状态以及将其连接到抗体的连接子如何影响其跨细胞膜的能力。结果表明，药物的电离状态会影响其膜通透性，因为带电分子在穿过膜的疏水核心时会遇到阻力。此外，该研究还揭示，连接子会增加药物的整体大小和疏水性，从而阻碍其向相邻细胞扩散。这一发现表明，连接子设计可通过限制其到达邻近癌细胞的能力，显著影响抗体药物偶联物（ADCs）的疗效。这些见解加深了我们对ADC机制的理解，并为优化针对乳腺癌的下一代ADC疗法提供了宝贵的基础。
