Drug Conjugates Based on a Monovalent Affibody Targeting Vector Can Efficiently Eradicate HER2 Positive Human Tumors in an Experimental Mouse Model; Cancers; Vol. 13, iss. 1
| Parent link: | Cancers Vol. 13, iss. 1.— 2020.— [85, 6 p.] |
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| Corporate Author: | |
| Other Authors: | , , , , , , |
| Summary: | Title screen The human epidermal growth factor receptor 2 (HER2) is frequently overexpressed in a variety of cancers and therapies targeting HER2 are routinely used in the clinic. Recently, small engineered scaffold proteins, such as affibody molecules, have shown promise as carriers of cytotoxic drugs, and these drug conjugates may become complements or alternatives to the current HER2-targeting therapies. Here, we investigated if a monovalent HER2-binding affibody molecule, ZHER2:2891, fused with a plasma half-life extending albumin binding domain (ABD), may be used as carrier of the cytotoxic maytansine derivate mcDM1. We found that the resulting drug conjugate, ZHER2:2891-ABD-E3-mcDM1, had strong affinity for its cognate molecular targets: HER2 and serum albumin. ZHER2:2891-ABD-E3-mcDM1 displayed potent cytotoxic activity towards cells with high HER2 expression, with IC50 values ranging from 0.6 to 33 nM. In vivo, an unspecific increase in uptake in the liver, imparted by the hydrophobic mcDM1, was counteracted by incorporation of hydrophilic and negatively charged glutamate residues near the site of mcDM1 conjugation. A dose-escalation experiment showed that increasing doses up to 15.1 mg/kg gave a proportional increase in uptake in xenografted HER2-overexpressing SKOV3 tumors, after which the tumors became saturated. Experimental therapy with four once-weekly injection of 10.3 or 15.1 mg/kg led to efficient regression of tumors in all animals and complete regression in some. Weight loss was detected for some animals in the group receiving the highest dose, suggesting that it was close to the maximum tolerated dose. In conclusion, the monovalent HER2-targeting affibody drug conjugate presented herein have potent anti-tumor activity in vivo. |
| Language: | English |
| Published: |
2020
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| Subjects: | |
| Online Access: | https://doi.org/10.3390/cancers13010085 |
| Format: | Electronic Book Chapter |
| KOHA link: | https://koha.lib.tpu.ru/cgi-bin/koha/opac-detail.pl?biblionumber=664907 |
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| 200 | 1 | |a Drug Conjugates Based on a Monovalent Affibody Targeting Vector Can Efficiently Eradicate HER2 Positive Human Tumors in an Experimental Mouse Model |f T. Xu, H. Ding, A. G. Vorobjeva (Vorobyeva) [et al.] | |
| 203 | |a Text |c electronic | ||
| 300 | |a Title screen | ||
| 320 | |a [References: 50 tit.] | ||
| 330 | |a The human epidermal growth factor receptor 2 (HER2) is frequently overexpressed in a variety of cancers and therapies targeting HER2 are routinely used in the clinic. Recently, small engineered scaffold proteins, such as affibody molecules, have shown promise as carriers of cytotoxic drugs, and these drug conjugates may become complements or alternatives to the current HER2-targeting therapies. Here, we investigated if a monovalent HER2-binding affibody molecule, ZHER2:2891, fused with a plasma half-life extending albumin binding domain (ABD), may be used as carrier of the cytotoxic maytansine derivate mcDM1. We found that the resulting drug conjugate, ZHER2:2891-ABD-E3-mcDM1, had strong affinity for its cognate molecular targets: HER2 and serum albumin. ZHER2:2891-ABD-E3-mcDM1 displayed potent cytotoxic activity towards cells with high HER2 expression, with IC50 values ranging from 0.6 to 33 nM. In vivo, an unspecific increase in uptake in the liver, imparted by the hydrophobic mcDM1, was counteracted by incorporation of hydrophilic and negatively charged glutamate residues near the site of mcDM1 conjugation. A dose-escalation experiment showed that increasing doses up to 15.1 mg/kg gave a proportional increase in uptake in xenografted HER2-overexpressing SKOV3 tumors, after which the tumors became saturated. Experimental therapy with four once-weekly injection of 10.3 or 15.1 mg/kg led to efficient regression of tumors in all animals and complete regression in some. Weight loss was detected for some animals in the group receiving the highest dose, suggesting that it was close to the maximum tolerated dose. In conclusion, the monovalent HER2-targeting affibody drug conjugate presented herein have potent anti-tumor activity in vivo. | ||
| 461 | |t Cancers | ||
| 463 | |t Vol. 13, iss. 1 |v [85, 6 p.] |d 2020 | ||
| 610 | 1 | |a электронный ресурс | |
| 610 | 1 | |a труды учёных ТПУ | |
| 610 | 1 | |a affibody molecule | |
| 610 | 1 | |a human epidermal growth factor receptor 2 | |
| 610 | 1 | |a HER2 | |
| 610 | 1 | |a SKOV3 | |
| 610 | 1 | |a DM1 | |
| 610 | 1 | |a albumin binding domain | |
| 701 | 1 | |a Xu |b T. |g Tianqi | |
| 701 | 1 | |a Ding |b H. |g Haozhong | |
| 701 | 1 | |a Vorobjeva (Vorobyeva) |b A. G. |c specialist in the field of medical technology |c Senior Researcher, Oncoteranostika Research Center, Tomsk Polytechnic University, Ph.D |f 1990- |g Anzhelika Grigorjevna |3 (RuTPU)RU\TPU\pers\46556 |9 22214 | |
| 701 | 1 | |a Oroujeni |b M. |g Maryam | |
| 701 | 1 | |a Orlova |b A. M. |c specialist in the field of medical technology |c Senior Researcher, Oncoteranostika Research Center, Tomsk Polytechnic University, Ph.D |f 1960- |g Anna Markovna |3 (RuTPU)RU\TPU\pers\46554 |9 22212 | |
| 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 | |
| 701 | 1 | |a Graslund |b T. |g Torbjorn | |
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