Affibody-derived drug conjugates targeting HER2: Effect of drug load on cytotoxicity and biodistribution

Haozhong Ding, Tianqi Xu, Jie Zhang, Vladimir Tolmachev, Maryam Oroujeni, Anna Orlova, Torbjörn Gräslund, Anzhelika Vorobyeva

Результат исследований: Материалы для журналаСтатьярецензирование

Аннотация

Affibody molecules hold great promise as carriers of cytotoxic drugs for cancer therapy due to their typically high affinity, easy production, and inherent control of the drug molecules’ loading and spatial arrangement. Here, the impact of increasing the drug load from one to three on the properties of an affibody drug conjugate targeting the human epidermal growth factor receptor 2 (HER2) was investigated. The affibody carrier was recombinantly expressed as a fusion to an albumin-binding domain (ABD) for plasma half-life extension. One or three cysteine amino acids were placed at the C-terminus to which cytotoxic mcDM1 molecules were conjugated. The resulting drug conjugates, ZHER2-ABD-mcDM1 and ZHER2-ABD-mcDM13, were characterized in vitro, and their biodistribution in mice carrying HER2-overexpressing SKOV3 xenografts was determined. Increasing the drug load from one to three led to a decrease in affinity for HER2, but a significantly more potent cytotoxic effect on SKOV3 cells with high HER2 expression. The difference in cytotoxic effect on other cell lines with high HER2 expression was not significant. In vivo, an increase in drug load led to a 1.45-fold higher amount of cytotoxic mcDM1 delivered to the tumors. The increase in drug load also led to more rapid hepatic clearance, warranting further optimization of the molecular design.

Язык оригиналаАнглийский
Номер статьи430
ЖурналPharmaceutics
Том13
Номер выпуска3
DOI
СостояниеОпубликовано - мар 2021

ASJC Scopus subject areas

  • Pharmaceutical Science

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