双特异性抗体
细胞因子
表位
CD3型
抗体
T细胞
抗原
细胞毒性
癌症研究
化学
效力
体外
免疫学
生物
分子生物学
免疫系统
单克隆抗体
生物化学
CD8型
作者
Nathan D. Trinklein,Duy Pham,Ute Schellenberger,Ben Buelow,Andrew Boudreau,Priya Choudhry,Starlynn Clarke,Kevin Dang,Katherine E. Harris,Suhasini Iyer,Brett Jorgensen,Payal Pratap,Udaya S. Rangaswamy,Harshad Ugamraj,Omid Vafa,Arun P. Wiita,Wim van Schooten,Roland Buelow,Shelley Force Aldred
出处
期刊:mAbs
[Informa]
日期:2019-02-20
卷期号:11 (4): 639-652
被引量:77
标识
DOI:10.1080/19420862.2019.1574521
摘要
T-cell-recruiting bispecific antibodies (T-BsAbs) have shown potent tumor killing activity in humans, but cytokine release-related toxicities have affected their clinical utility. The use of novel anti-CD3 binding domains with more favorable properties could aid in the creation of T-BsAbs with improved therapeutic windows. Using a sequence-based discovery platform, we identified new anti-CD3 antibodies from humanized rats that bind to multiple epitopes and elicit varying levels of T-cell activation. In T-BsAb format, 12 different anti-CD3 arms induce equivalent levels of tumor cell lysis by primary T-cells, but potency varies by a thousand-fold. Our lead CD3-targeting arm stimulates very low levels of cytokine release, but drives robust tumor antigen-specific killing in vitro and in a mouse xenograft model. This new CD3-targeting antibody underpins a next-generation T-BsAb platform in which potent cytotoxicity is uncoupled from high levels of cytokine release, which may lead to a wider therapeutic window in the clinic.
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