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<p>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.</p>

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In silico decrypting of the bystander effect in antibody–drug conjugates for breast cancer therapy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月6日

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  • Víctor L. Cruz,
  • Jorge Duro-Sánchez,
  • Emma Franco-Mateos,
  • Laura García-Estévez,
  • José Pérez-García,
  • María Gion,
  • Laia Garrigós,
  • Patricia Cortez,
  • Cristina Saavedra,
  • Patricia Gómez,
  • Carolina Ortiz,
  • Arantxa Aguinagalde,
  • Javier Ramos,
  • Javier Cortés,
  • Juan F. Vega

摘要

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.