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Title: “Scalable, Continuous Directed Evolution of Nanobody-Based GPCR Agonists”

Advisory Committee: Mo Khalil, PhD – BU BME (Advisor) John Ngo, PhD – BU BME (Chair) Wilson Wong, PhD – BU BME Chang Liu, PhD – UC Irvine BME

Abstract: G protein-coupled receptors (GPCRs) are one of the most common signaling structures in the human body and are therefore a highly prominent drug target. Despite fully one-third of all FDA approved drugs targeting GPCRs, more than 75% of all non-olfactory GPCRs remain undrugged, including many well-validated targets. GPCRs have historically been drugged with small molecules and peptides, but these suffer from specificity and pharmacokinetic challenges, restricting the scope of GPCRs they can target. Antibodies and nanobodies offer a promising alternative due to their exquisite specificity and robust pharmacokinetics. However, current antibody/nanobody discovery techniques lack the throughput needed to uncover rare variants capable of precisely modulating GPCR function for therapy. In this work, I will create a novel discovery platform coupling OrthoRep, a powerful new continuous directed evolution system, with a growth-based functional selection for GPCR activation to deeply search nanobody sequence space and evolve variants with agonist activity. I aim to demonstrate the power of this platform by evolving the first nanobody agonist for the clinically relevant GLP-1 receptor.