AUTHOR=Dunlap Tyler , Cao Yanguang TITLE=Physiological Considerations for Modeling in vivo Antibody-Target Interactions JOURNAL=Frontiers in Pharmacology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.856961 DOI=10.3389/fphar.2022.856961 ISSN=1663-9812 ABSTRACT=

The number of therapeutic antibodies in development pipelines is increasing rapidly. Despite superior success rates relative to small molecules, therapeutic antibodies still face many unique development challenges. There is often a translational gap from their high target affinity and specificity to the therapeutic effects. Tissue microenvironment and physiology critically influence antibody-target interactions contributing to apparent affinity alterations and dynamic target engagement. The full potential of therapeutic antibodies will be further realized by contextualizing antibody-target interactions under physiological conditions. Here we review how local physiology such as physical stress, biological fluid, and membrane characteristics could influence antibody-target association, dissociation, and apparent affinity. These physiological factors in the early development of therapeutic antibodies are valuable toward rational antibody engineering, preclinical candidate selection, and lead optimization.