Comparison of HER2-targeted affibody conjugates loaded with auristatin- and maytansine-derived drugs; Journal of Controlled Release; Vol. 355

Comparison of HER2-targeted affibody conjugates loaded with auristatin- and maytansine-derived drugs; Journal of Controlled Release; Vol. 355

Bibliographic Details
Parent link:Journal of Controlled Release
Vol. 355.— 2023.— [P. 515-527]
Corporate Author: Национальный исследовательский Томский политехнический университет Исследовательская школа химических и биомедицинских технологий (ИШХБМТ)
Other Authors: Yin Wen, Xu Tianqi, Ding Haozhong, Zhang Jie, Bodenko V. V. Vitalina Vasiljevna, Tretyakova (Tretjyakova) M. S. Maria Sergeevna, Belousov M. V. Mikhail Valerievich, Liu Yongsheng, Oroujeni M. Maryam, Orlova A. M. Anna Markovna, Tolmachev V. M. Vladimir Maksimilianovich, Graslund T. Torbjorn, Vorobjeva (Vorobyeva) A. G. Anzhelika Grigorjevna
Summary:Title screen
Treatment with antibody drug conjugates targeting receptors over-expressed on cancer cells is well established for clinical use in several types of cancer, however, resistance often occurs motivating the development of novel drugs. We have recently investigated a drug conjugate consisting of an affibody molecule targeting the human epidermal growth factor receptor 2 (HER2), fused to an albumin-binding domain (ABD) for half-life extension, loaded with the cytotoxic maytansine derivative DM1. In this study, we investigated the impact of the cytotoxic payload on binding properties, cytotoxicity and biodistribution by comparing DM1 with the auristatins MMAE and MMAF, as part of the drug conjugate. All constructs had specific and high affinity binding to HER2, human and mouse albumins with values in the low- to sub-nM range. ZHER2-ABD-mcMMAF demonstrated the most potent cytotoxic effect on several HER2-over-expressing cell lines. In an experimental therapy study, the MMAF-based conjugate provided complete tumor regression in 50% of BALB/c nu/nu mice bearing HER2-over-expressing SKOV3 tumors at a 2.9 mg/kg dose, while the same dose of ZHER2-ABD-mcDM1 provided only a moderate anti-tumor effect. A comparison with the non-targeting ZTaq-ABD-mcMMAF control demonstrated HER2-targeting specificity. In conclusion, a combination of potent cytotoxicity in vitro, with minimal uptake in normal organs in vivo, and efficient delivery to tumors provided a superior anti-tumor effect of ZHER2-ABD-mcMMAF, while maintaining a favorable toxicity profile with no observed adverse effects.
Режим доступа: по договору с организацией-держателем ресурса
Language:English
Published: 2023
Subjects:
электронный ресурс
труды учёных ТПУ
Affibody molecule
drug conjugate
DM1
HER2
cancer
therapy
Online Access:https://doi.org/10.1016/j.jconrel.2023.02.005
Format: Electronic Book Chapter
KOHA link:https://koha.lib.tpu.ru/cgi-bin/koha/opac-detail.pl?biblionumber=669227

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