Abstract

Cell surface proteins are key regulators of cancer and immune cell signaling, metabolism, and interactions with the surrounding environment. A promising approach to modulating their function is through the control of endocytosis and intracellular trafficking. Under normal physiological conditions, cells use these processes to maintain membrane protein homeostasis and attenuate signaling, yet their therapeutic potential has only recently begun to be explored. In this talk, I will discuss how bispecific antibodies can be designed to modularly control membrane protein endocytosis and signaling, including those of growth factor receptors and G protein–coupled receptors, and describe the underlying mechanisms by which these molecules function, with comparisons to traditional antagonists and their potential clinical implications. I will also present a protein engineering approach to develop synthetic protein binders that recognize tyrosine-phosphorylated signaling motifs, including sites in PD-1 and LAT , regulators of T cell activity. Using these binders, we have built sensors and biocircuits to elucidate PD-1 activation with spatiotemporal specificity, investigate mechanisms of new PD-1 modulators such as anti–PD-1/VEGF bispecific antibodies, and reprogram signaling outcomes to create enhanced CAR -T cells.