西妥昔单抗
抗体
体内
蛋白酵素
表皮生长因子受体
癌症研究
医学
离体
治疗指标
抗原
免疫学
化学
单克隆抗体
药理学
癌症
生物
药品
内科学
生物化学
生物技术
酶
作者
Luc Desnoyers,Olga Vasiljeva,Jennifer Richardson,Annie Yang,Elizabeth Menendez,Tony W. Liang,Chihunt Wong,Paul H. Bessette,Kathy Kamath,Stephen Moore,Jason Sagert,Daniel R. Hostetter,Fei Han,Jason Gee,Jeanne Flandez,Kate Markham,Margaret Nguyen,Michael Krimm,Kenneth R. Wong,Shouchun Liu,Patrick S. Daugherty,James W. West,Henry B. Lowman
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2013-10-16
卷期号:5 (207)
被引量:206
标识
DOI:10.1126/scitranslmed.3006682
摘要
Target-mediated toxicity constitutes a major limitation for the development of therapeutic antibodies. To redirect the activity of antibodies recognizing widely distributed targets to the site of disease, we have applied a prodrug strategy to create an epidermal growth factor receptor (EGFR)-directed Probody therapeutic-an antibody that remains masked against antigen binding until activated locally by proteases commonly active in the tumor microenvironment. In vitro, the masked Probody showed diminished antigen binding and cell-based activities, but when activated by appropriate proteases, it regained full activity compared to the parental anti-EGFR antibody cetuximab. In vivo, the Probody was largely inert in the systemic circulation of mice, but was activated within tumor tissue and showed antitumor efficacy that was similar to that of cetuximab. The Probody demonstrated markedly improved safety and increased half-life in nonhuman primates, enabling it to be dosed safely at much higher levels than cetuximab. In addition, we found that both Probody-responsive xenograft tumors and primary tumor samples from patients were capable of activating the Probody ex vivo. Probodies may therefore improve the safety profile of therapeutic antibodies without compromising efficacy of the parental antibody and may enable the wider use of empowered antibody formats such as antibody-drug conjugates and bispecifics.
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