Antibody therapeutics, antibody engineering, and the merits of protein stability

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.