Novel Silyl Ether-Based Acid-Cleavable Antibody-MMAE Conjugates with Appropriate Stability and Efficacy
Antibody-drug conjugate (ADC) is a novel efficient drug delivery system that has been successfully used in clinical practice, and it has become a research hotspot in the anti-tumor drug field. Acid-cleavable linkers were first used in clinical ADCs, but their structural variety (e.g., hydrazone and...
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| Format: | Article |
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MDPI AG
2019-07-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/7/957 |
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| author | Yanming Wang Shiyong Fan Dian Xiao Fei Xie Wei Li Wu Zhong Xinbo Zhou |
| author_facet | Yanming Wang Shiyong Fan Dian Xiao Fei Xie Wei Li Wu Zhong Xinbo Zhou |
| author_sort | Yanming Wang |
| collection | DOAJ |
| description | Antibody-drug conjugate (ADC) is a novel efficient drug delivery system that has been successfully used in clinical practice, and it has become a research hotspot in the anti-tumor drug field. Acid-cleavable linkers were first used in clinical ADCs, but their structural variety (e.g., hydrazone and carbonate) is still limited, and their stability is usually insufficient. Designing novel acid-cleavable linkers for the conjugation of the popular cytotoxin monomethyl auristatin E (MMAE) has always been a significant topic. In this paper, we generate a novel, silyl ether-based acid-cleavable antibody-MMAE conjugate, which skillfully achieves efficient combination of amino-conjugated MMAE with the acid-triggered silyl ether group by introducing <i>p</i>-hydroxybenzyl alcohol (PHB). The stability, acid-dependence cleavage, effective mechanism, efficacy and safety of the resulting ADC were systematically studied; the results show that it exhibits a significant improvement in stability, while maintaining appropriate efficacy and controlled therapeutic toxicity. This strategy is expected to expand a new type of acid-cleavable linkers for the development of ADCs with highly potent payloads. |
| first_indexed | 2024-03-12T10:01:13Z |
| format | Article |
| id | doaj.art-3c0a7167bad54ccca079394631d2b6a1 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T10:01:13Z |
| publishDate | 2019-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-3c0a7167bad54ccca079394631d2b6a12023-09-02T11:40:12ZengMDPI AGCancers2072-66942019-07-0111795710.3390/cancers11070957cancers11070957Novel Silyl Ether-Based Acid-Cleavable Antibody-MMAE Conjugates with Appropriate Stability and EfficacyYanming Wang0Shiyong Fan1Dian Xiao2Fei Xie3Wei Li4Wu Zhong5Xinbo Zhou6National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaAntibody-drug conjugate (ADC) is a novel efficient drug delivery system that has been successfully used in clinical practice, and it has become a research hotspot in the anti-tumor drug field. Acid-cleavable linkers were first used in clinical ADCs, but their structural variety (e.g., hydrazone and carbonate) is still limited, and their stability is usually insufficient. Designing novel acid-cleavable linkers for the conjugation of the popular cytotoxin monomethyl auristatin E (MMAE) has always been a significant topic. In this paper, we generate a novel, silyl ether-based acid-cleavable antibody-MMAE conjugate, which skillfully achieves efficient combination of amino-conjugated MMAE with the acid-triggered silyl ether group by introducing <i>p</i>-hydroxybenzyl alcohol (PHB). The stability, acid-dependence cleavage, effective mechanism, efficacy and safety of the resulting ADC were systematically studied; the results show that it exhibits a significant improvement in stability, while maintaining appropriate efficacy and controlled therapeutic toxicity. This strategy is expected to expand a new type of acid-cleavable linkers for the development of ADCs with highly potent payloads.https://www.mdpi.com/2072-6694/11/7/957antibody-drug conjugatelinkeracid-cleavablesilyl ethermonomethyl auristatin E |
| spellingShingle | Yanming Wang Shiyong Fan Dian Xiao Fei Xie Wei Li Wu Zhong Xinbo Zhou Novel Silyl Ether-Based Acid-Cleavable Antibody-MMAE Conjugates with Appropriate Stability and Efficacy Cancers antibody-drug conjugate linker acid-cleavable silyl ether monomethyl auristatin E |
| title | Novel Silyl Ether-Based Acid-Cleavable Antibody-MMAE Conjugates with Appropriate Stability and Efficacy |
| title_full | Novel Silyl Ether-Based Acid-Cleavable Antibody-MMAE Conjugates with Appropriate Stability and Efficacy |
| title_fullStr | Novel Silyl Ether-Based Acid-Cleavable Antibody-MMAE Conjugates with Appropriate Stability and Efficacy |
| title_full_unstemmed | Novel Silyl Ether-Based Acid-Cleavable Antibody-MMAE Conjugates with Appropriate Stability and Efficacy |
| title_short | Novel Silyl Ether-Based Acid-Cleavable Antibody-MMAE Conjugates with Appropriate Stability and Efficacy |
| title_sort | novel silyl ether based acid cleavable antibody mmae conjugates with appropriate stability and efficacy |
| topic | antibody-drug conjugate linker acid-cleavable silyl ether monomethyl auristatin E |
| url | https://www.mdpi.com/2072-6694/11/7/957 |
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