Comparison of HER2-targeted affibody conjugates loaded with auristatin- and maytansine-derived drugs; Journal of Controlled Release; Vol. 355
| Parent link: | Journal of Controlled Release Vol. 355.— 2023.— [P. 515-527] |
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| সংস্থা লেখক: | |
| অন্যান্য লেখক: | , , , , , , , , , , , , |
| সংক্ষিপ্ত: | 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 |
| ভাষা: | ইংরেজি |
| প্রকাশিত: |
2023
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| বিষয়গুলি: | |
| অনলাইন ব্যবহার করুন: | https://doi.org/10.1016/j.jconrel.2023.02.005 |
| বিন্যাস: | বৈদ্যুতিক গ্রন্থের অধ্যায় |
| KOHA link: | https://koha.lib.tpu.ru/cgi-bin/koha/opac-detail.pl?biblionumber=669227 |
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| 200 | 1 | |a Comparison of HER2-targeted affibody conjugates loaded with auristatin- and maytansine-derived drugs |f Yin Wen, Xu Tianqi, Ding Haozhong [et al.] | |
| 203 | |a Text |c electronic | ||
| 300 | |a Title screen | ||
| 320 | |a [References: 48 tit.] | ||
| 330 | |a 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. | ||
| 333 | |a Режим доступа: по договору с организацией-держателем ресурса | ||
| 461 | |t Journal of Controlled Release | ||
| 463 | |t Vol. 355 |v [P. 515-527] |d 2023 | ||
| 610 | 1 | |a электронный ресурс | |
| 610 | 1 | |a труды учёных ТПУ | |
| 610 | 1 | |a Affibody molecule | |
| 610 | 1 | |a drug conjugate | |
| 610 | 1 | |a DM1 | |
| 610 | 1 | |a HER2 | |
| 610 | 1 | |a cancer | |
| 610 | 1 | |a therapy | |
| 701 | 0 | |a Yin Wen | |
| 701 | 0 | |a Xu Tianqi | |
| 701 | 0 | |a Ding Haozhong | |
| 701 | 0 | |a Zhang Jie | |
| 701 | 1 | |a Bodenko |b V. V. |c pharmacist |c engineer at Tomsk Polytechnic University |f 1997- |g Vitalina Vasiljevna |9 88553 | |
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| 701 | 1 | |a Belousov |b M. V. |c chemist |c Professor of Tomsk Polytechnic University, Doctor of Pharmaceutical Sciences |f 1963- |g Mikhail Valerievich |3 (RuTPU)RU\TPU\pers\45418 |9 21924 | |
| 701 | 0 | |a Liu Yongsheng | |
| 701 | 1 | |a Oroujeni |b M. |g Maryam | |
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| 701 | 1 | |a Tolmachev |b V. M. |c specialist in the field of medical technology |c Director of the Research Center "Oncoteranostika", Tomsk Polytechnic University, Ph.D |f 1961- |g Vladimir Maksimilianovich |3 (RuTPU)RU\TPU\pers\46552 |9 22210 | |
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