An amphipol‐stabilized multi‐pass transmembrane protein as an immunogen to generate mouse memory B cells against native VMAT2

Multi‐pass transmembrane proteins (MPTPs) are essential for sensing and processing cellular signals and are the primary drug targets of more than half of the approved drugs, the majority being small molecules. However, monoclonal antibodies with favorable properties in modulating MPTPs are rare. Such antibody discovery is limited by the challenging preparation of correctly folded antigens and the generation of antibodies against the natural conformation of MPTPs. Here, we developed an amphipol‐trapped antigen as an immunogen and induced efficient mouse memory B cell responses. We generated antibodies unbiasedly by culturing single memory B cells and characterized their specificities. We implemented our strategy to generate high‐affinity antibodies against the native conformation of vesicular monoamine transporter 2 (VMAT2; also known as SLC18A2), demonstrating the potential use in discovering antibodies against MPTPs for therapeutics.