结合
体内分布
药品
抗体
化学
曲妥珠单抗
共轭体系
赖氨酸
抗体-药物偶联物
药理学
组合化学
单克隆抗体
生物化学
医学
免疫学
氨基酸
体外
癌症
内科学
聚合物
有机化学
数学分析
数学
乳腺癌
作者
Jöri E. Wehrmüller,Julia C. Frei,Torsten Hechler,Michael Kulke,Andreas Pahl,Martin Béhé,Roger Schibli,Philipp R. Spycher
标识
DOI:10.1002/cbic.202400511
摘要
Homogeneous, site‐specifically conjugated antibodies have shown to result in antibody‐drug conjugates (ADCs) with improved efficacy and tolerability compared to stochastically conjugated ADCs. However, precisely controlling the drug‐load as well as attaching multiple payload moieties on the antibody remains challenging. Here, we demonstrate the simple and direct modification of native IgG‐antibodies at the residue glutamine 295 (Q295) without the need for any protein engineering at flexible drug‐to‐antibody ratios of one or multiple payloads. The conjugation is enabled through short, positively charged lysine containing peptides and native, commercially available microbial transglutaminase. In proof‐of‐concept studies, HER2‐targeting ADCs based on trastuzumab were generated with drug‐to‐antibody ratios (DARs) of 2 and 4 of the same or different payloads using orthogonal conjugation chemistries. Quantitative biodistribution studies performed with 111In‐radiolabeled conjugates showed high tumour uptake and low accumulation of radioactivity in non‐targeted tissues. A single dose study of trastuzumab conjugated to the highly potent payload α‐Amanitin demonstrated complete and long‐lasting tumour remissions and was well‐tolerated at all dose levels tested.
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