喜树碱
连接器
体内
化学
有效载荷(计算)
组合化学
抗体-药物偶联物
药理学
抗体
单克隆抗体
生物化学
计算机科学
生物
免疫学
计算机网络
生物技术
网络数据包
操作系统
作者
Susanne Schmitt,Paul Machui,Isabelle Mai,Sabine Herterich,Swetlana Wunder,Philipp Cyprys,Marcus Gerlach,Philipp Ochtrop,Christian P. R. Hackenberger,Dominik Schumacher,Jonas Helma,Annette M. Vogl,Marc‐André Kasper
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2023-10-12
卷期号:23 (2): 199-211
标识
DOI:10.1158/1535-7163.mct-23-0359
摘要
Topoisomerase I (TOP1) Inhibitors constitute an emerging payload class to engineer Antibody-Drug-Conjugates (ADCs) as next-generation biopharmaceutical for cancer treatment. Existing ADCs are utilizing camptothecin payloads with lower potency and suffer from limited stability in circulation. With this study, we introduce a novel camptothecin-based linker-payload platform based on the highly potent camptothecin derivative exatecan. First, we describe general challenges that arise from the hydrophobic combination of exatecan and established dipeptidyl p-aminobenzyl-carbamate (PAB) cleavage sites such as reduced antibody conjugation yields and ADC aggregation. After evaluating several linker-payload structures we identified ethynyl-phosphonamidates in combination with a discrete PEG24 chain to compensate for the hydrophobic PAB-exatecan moiety. Furthermore, we demonstrate that the identified linker-payload structure enables the construction of highly loaded DAR8 ADCs with excellent solubility properties. Head-to-head comparison to Enhertu, an approved camptothecin-based ADC, revealed improved target-mediated killing of tumor cells, excellent bystander killing, drastically improved linker stability in vitro and in vivo and superior in vivo efficacy over four tested dose levels in a xenograft model. Moreover, we show that ADCs based on the novel exatecan linker-payload platform exhibit antibody-like pharmacokinetic properties, even when the ADCs are highly loaded with eight drug molecules per antibody. This ADC platform constitutes a new and general solution to deliver TOP1-inhibitors with highest efficiency to the site of the tumor, independent of the antibody and its target, and is thereby broadly applicable to various cancer indications.
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