Demarest Stephen J, Glaser Scott M
Biogen Idec, 5200 Research Place, San Diego, CA 92122, USA.
Curr Opin Drug Discov Devel. 2008 Sep;11(5):675-87.
Antibodies are highly soluble, multidomain proteins that are well suited for biopharmaceutical development; however, engineering antibodies to perform novel activities or to have enhanced clinical utility can have a detrimental effect on their biophysical properties. Various innovative designs, such as single-chain variable fragments (scFvs) and domain antibodies (dAbs), have been utilized to obtain the antigen-binding properties of natural antibodies, while using a minimal amount of the polypeptide sequence of an antibody. These designs can be used for generating diverse antibody libraries to support discovery and optimization and also serve as excellent building blocks for constructing more complex protein therapeutics, such as bispecific antibodies. However, engineered antibody-like proteins, including scFvs, are often unstable and prone to aggregation, compromising both protein production and quality. Research over the past few years has enhanced our understanding of how interdomain interactions within antibodies contribute to protein stability. This knowledge and sustained research to develop methods for modifying antibody fragments to improve stability have begun to have a positive impact on the quality of antibody libraries for discovery purposes and the viability of highly engineered proteins, such as bispecific antibodies, as therapeutics.
抗体是高度可溶的多结构域蛋白，非常适合生物制药开发；然而，对抗体进行工程改造以使其具有新活性或增强临床效用可能会对其生物物理性质产生不利影响。人们已采用各种创新设计，如单链可变片段（scFv）和结构域抗体（dAb），以获得天然抗体的抗原结合特性，同时使用最少的抗体多肽序列。这些设计可用于生成多样化的抗体文库，以支持发现和优化，还可作为构建更复杂蛋白质疗法（如双特异性抗体）的优良构建模块。然而，包括scFv在内的工程化抗体样蛋白通常不稳定且易于聚集，这会影响蛋白质的生产和质量。过去几年的研究增进了我们对抗体结构域间相互作用如何影响蛋白质稳定性的理解。这方面的知识以及为改进抗体片段稳定性而开发修饰方法的持续研究，已开始对用于发现目的的抗体文库质量以及高度工程化蛋白质（如双特异性抗体）作为治疗药物的可行性产生积极影响。
