In-silico Decrypting of the Bystander Effect in Antibody-Drug Conjugates for Breast Cancer Therapy

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," where nearby cancer cells are also affected by passive diffusion. However, the mechanisms behind this effect remain unclear. Using computer simulations, we investigated how the drug's ionization state and the linker connecting it to the antibody influence its ability to cross cell membranes. Our results show that the ionization state of the drug impacts its ability to pass through the membrane, as charged molecules face resistance moving through the membrane’s hydrophobic core. Moreover, we discovered that the linker increases the drug’s size and hydrophobicity, hindering its release to nearby cells. This suggests that the linker design can limit ADC efficacy by restricting its reach to neighboring cancer cells. These insights enhance our understanding of ADC function and provide a foundation for optimizing future ADC therapies for breast cancer.