Department of Molecular Medicine, Beckman Research Institute of City of Hope, 1710 Flower St., Duarte, CA, 91010, USA.
Xencor, 111W. Lemon Ave., Monrovia, CA, 91016, USA.
Nat Commun. 2018 Apr 20;9(1):1580. doi: 10.1038/s41467-018-03976-5.
Because monoclonal antibodies (mAbs) have exceptional specificity and favorable pharmacology, substantial efforts have been made to functionalize them, either with potent cytotoxins, biologics, radionuclides, or fluorescent groups for therapeutic benefit and/or use as theranostic agents. To exploit our recently discovered meditope-Fab interaction as an alternative means to efficiently functionalize mAbs, we used insights from the structure to enhance the affinity and lifetime of the interaction by four orders of magnitude. To further extend the lifetime of the complex, we created a mechanical bond by incorporating an azide on the meditope, threading the azide through the Fab, and using click chemistry to add a steric group. The mechanically interlocked, meditope-Fab complex retains antigen specificity and is capable of imaging tumors in mice. These studies indicate it is possible to "snap" functionality onto mAbs, opening the possibility of rapidly creating unique combinations of mAbs with an array of cytotoxins, biologics, and imaging agents.
由于单克隆抗体（mAbs）具有出色的特异性和良好的药理学特性，因此人们已经做出了大量努力来对其进行功能化，无论是将其与有效的细胞毒素、生物制剂、放射性核素还是荧光团结合，以实现治疗益处和/或作为治疗诊断剂使用。为了利用我们最近发现的抗原决定簇-Fab 相互作用作为有效功能化 mAbs 的替代方法，我们利用结构方面的见解，通过提高亲和力和相互作用的半衰期将其提高了四个数量级。为了进一步延长复合物的半衰期，我们在抗原决定簇上引入了叠氮化物，将叠氮化物穿过 Fab，并使用点击化学添加了一个位阻基团，从而形成了机械键。机械互锁的抗原决定簇-Fab 复合物保留了抗原特异性，并能够在小鼠中成像肿瘤。这些研究表明，可以将功能“卡合”到 mAbs 上，从而有可能快速创建具有一系列细胞毒素、生物制剂和成像剂的独特 mAbs 组合。
