Discovery of Therapeutic Antibodies Targeting Complex Multi-Spanning Membrane Proteins

Complex integral membrane proteins, which are embedded in the cell surface lipid bilayer by multiple transmembrane spanning polypeptides, encompass families of proteins that are important target classes for drug discovery. These protein families include G protein-coupled receptors, ion channels, transporters, enzymes, and adhesion molecules. The high specificity of monoclonal antibodies and the ability to engineer their properties offers a significant opportunity to selectively bind these target proteins, allowing direct modulation of pharmacology or enabling other mechanisms of action such as cell killing. Isolation of antibodies that bind these types of membrane proteins and exhibit the desired pharmacological function has, however, remained challenging due to technical issues in preparing membrane protein antigens suitable for enabling and driving antibody drug discovery strategies. In this article, we review progress and emerging themes in defining discovery strategies for a generation of antibodies that target these complex membrane protein antigens. We also comment on how this field may develop with the emerging implementation of computational techniques, artificial intelligence, and machine learning.