CAREER: Engineered multispecific antibodies to interrogate and manipulate immune checkpoint protein trafficking

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Cancers can suppress the immune response by binding specific proteins on the surface of T-cells. This binding turns off the tumor-killing function of the T-cells. Antibodies designed to block that binding are known as checkpoint inhibitors. Checkpoint inhibitors allow the normal immune response so T-cells can attack the cancerous cells. Unfortunately, checkpoint inhibitor treatment is only approved for about a dozen cancer types and is effective in a minority of cases. Designing and testing antibodies that block immune checkpoint pathways through a unique mechanism is the focus of this project. Enhancing our understanding of the dynamics of the immune response will aid in the design of more effective cancer therapeutics. The research program is interwoven with an education and outreach program. Baltimore high school students will engage in interactive research experiences, and a workshop will engage local students and their families in protein engineering. Collaboration with Baltimore teachers will integrate engineering into the K-12 curriculum and inspire students to pursue careers at the interface of engineering, immunology, and medicine.Clinical antibody drugs competitively inhibit interactions between surface-bound immune checkpoint proteins and their activating ligands. This project will instead target the molecular trafficking behavior of the checkpoint proteins before they reach the cell surface. Engaging multiple epitopes on a single transmembrane protein can induce clustering and down-regulation, eliminating immune checkpoint proteins from the cell surface. This mobilizes the immune response. The research objective of this project is to discover and design multi-specific down-regulating antibodies (MSDR Abs) targeting immune checkpoint proteins, use them to explore molecular trafficking, and evaluate their effects on the immune system. MSDR Abs will enable molecular characterization of immune checkpoint pathways and help elucidate the mechanisms underlying resistance to current therapeutics. The proposed work will also lay the foundation for development of custom-designed proteins that enact a distinctive trafficking-based mechanism and have great potential as cancer therapies. Moreover, the modular platform developed herein can be readily extended to other biological systems for a range of research and medical applications.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.