Abstract
The success of antibody therapeutics is strongly influenced by their multifunctional nature that couples antigen recognition mediated by their variable regions with effector functions and half-life extension mediated by a subset of their constant regions. Nevertheless, the monospecific IgG format is not optimal for many therapeutic applications, and this has led to the design of a vast number of unique multispecific antibody formats that enable targeting of multiple antigens or multiple epitopes on the same antigen. Despite the diversity of these formats, a common challenge in generating multispecific antibodies is that they display suboptimal physical and chemical properties relative to conventional IgGs and are more difficult to develop into therapeutics. Here we review advances in the design and engineering of multispecific antibodies with drug-like properties, including favorable stability, solubility, viscosity, specificity and pharmacokinetic properties. We also highlight emerging experimental and computational methods for improving the next generation of multispecific antibodies, as well as their constituent antibody fragments, with natural IgG-like properties. Finally, we identify several outstanding challenges that need to be addressed to increase the success of multispecific antibodies in the clinic.
Highlights
IntroductionAntibodies are among the most well-established biologics and are widely employed as therapeutics
Antibodies are among the most well-established biologics and are widely employed as therapeutics.Their success as therapeutics is largely due to their unique combination of properties, including their favorable activities, safety profiles, and physical and chemical properties
While electrostatic interactions typically drive reversible self-association in monoclonal antibodies, this study presents an example in which reversible self-association is predominantly induced by short-range hydrophobic interactions rather than long-range electrostatic interactions
Summary
Antibodies are among the most well-established biologics and are widely employed as therapeutics. Their success as therapeutics is largely due to their unique combination of properties, including their favorable activities, safety profiles, and physical and chemical properties ( known as developability properties). The desirable developability properties of antibodies are due to their high folding stabilities, high solubilities, low viscosities and high chemical stabilities. The combination of these key properties has led to >80 approved antibody drugs and hundreds more in clinical trials [1]
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