TetraGenetics Inc, Arlington, MA, USA.
Department of Microbiology and Microbiology, Cornell University, Ithaca, NY, USA.
Handb Exp Pharmacol. 2021;267:507-545. doi: 10.1007/164_2021_464.
Monoclonal antibodies combine specificity and high affinity binding with excellent pharmacokinetic properties and are rapidly being developed for a wide range of drug targets including clinically important potassium ion channels. Nonetheless, while therapeutic antibodies come with great promise, K channels represent particularly difficult targets for biologics development for a variety of reasons that include their dynamic structures and relatively small extracellular loops, their high degree of sequence conservation (leading to immune tolerance), and their generally low-level expression in vivo. The process is made all the more difficult when large numbers of antibody candidates must be screened for a given target, or when lead candidates fail to cross-react with orthologous channels in animal disease models due to their highly selective binding properties. While the number of antibodies targeting potassium channels in preclinical or clinical development is still modest, significant advances in the areas of protein expression and antibody screening are converging to open the field to an avalanche of new drugs. Here, the opportunities and constraints associated with the discovery of antibodies against K channels are discussed, with an emphasis on novel technologies that are opening the field to exciting new possibilities for biologics development.
单克隆抗体结合了特异性和高亲和力结合与优异的药代动力学特性，并且正在迅速针对包括临床重要的钾离子通道在内的广泛药物靶点进行开发。尽管治疗性抗体具有巨大的潜力，但由于多种原因，K 通道对于生物制剂的开发仍然是一个特别困难的靶点，这些原因包括其动态结构和相对较小的细胞外环、高度的序列保守性（导致免疫耐受）以及其在体内的普遍低水平表达。当必须针对给定的靶点筛选大量的抗体候选物时，或者当先导候选物由于其高度选择性的结合特性而未能与动物疾病模型中的同源通道发生交叉反应时，情况就变得更加困难。尽管针对钾通道的处于临床前或临床开发阶段的抗体数量仍然不多，但在蛋白质表达和抗体筛选领域的重大进展正在汇聚，为大量新药的开发开辟了道路。在这里，讨论了针对 K 通道发现抗体的机会和限制，重点介绍了正在为生物制剂开发开辟令人兴奋的新可能性的新技术。
