Engineering multivalent and multispecific protein therapeutics

Abstract

In nature, there are a wide array of proteins that utilize the principles of multivalency and multispecificity to ensure optimal biological function. Their mechanisms of action have served as inspiration for the development of next-generation protein therapeutics with improved efficacy and safety profiles. Protein therapeutics leverage the inherent affinity and specificity of protein-protein interactions, offering an effective approach for targeting and modulating biochemical pathways. An increased molecular understanding of biological processes that underlie disease pathologies, as well as the advent of new protein engineering platforms, has elevated the sophistication of protein therapeutics entering the clinical pipeline. Here, we discuss the main advantages conferred by multivalency and multispecificity as they are related to protein therapeutics, namely increased targeting affinity through avidity effects, and selectivity for a diseased versus normal state. These aspects lead to greater therapeutic control over an intended biological response, with the potential for reduced side effects. In this chapter, we describe the basic biophysical principles underlying multivalency and multispecificity and discuss how they influence protein design parameters. Finally, we consider how one can utilize these concepts to develop protein therapeutics that address challenging biomedical problems.