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- Title
Novel Silyl Ether-Based Acid-Cleavable Antibody-MMAE Conjugates with Appropriate Stability and Efficacy.
- Authors
Wang, Yanming; Fan, Shiyong; Xiao, Dian; Xie, Fei; Li, Wei; Zhong, Wu; Zhou, Xinbo
- Abstract
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 p-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.
- Subjects
IMMUNOGLOBULIN analysis; ALCOHOLS (Chemical class); ANIMAL experimentation; ANTINEOPLASTIC agents; DRUG delivery systems; DRUG stability; ETHERS; MICE; MOLECULAR structure; PATIENT safety; TREATMENT effectiveness
- Publication
Cancers, 2019, Vol 11, Issue 7, p957
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers11070957