SBIR Phase II: A platform for identifying antibodies that modulate human membrane receptors involved in disease

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase II project is to develop a drug discovery platform that will identify novel types of antibody therapeutics. The goal is to use antibodies to increase or decrease the activity of a type of cell signaling receptor called "G protein-coupled receptors" (GPCRs). There are more than 400 non-olfactory human GPCRs that are involved in all aspects of health and disease, including cancers, autoimmune diseases, pain, inflammation, and others. About 25% of GPCRs have been targeted by approved small molecule drugs, but efforts for the remaining have often failed because of the inability of small molecules to distinguish between similar GPCRs. Antibody drugs can overcome this hurdle because of their much higher specificity for their targets. This project will bring to commercialization the first technology that directly identifies antibodies that modulate GPCR function. These antibodies will impact healthcare by enabling therapies for diseases with poor or no current treatments. They also will impact scientific understanding by enabling the study of GPCR-related physiology and disease. The commercial impacts are potentially very large. The GPCR drug market is over $100B, and most antibody therapeutics have annual sales over $1B. The platform described here could enable dozens of novel GPCR antibody therapeutics, creating value for patients, society, and co-development partners. The intellectual merit of this SBIR Phase II project is to develop a drug discovery technology for discovering antibodies that modulate G-protein coupled receptors (GPCRs). Current methods are limited because GPCR antigens are often not properly folded, and because antibodies are selected by how tightly they bind GPCRs, rather than by the effect they exert. Those that bind typically do not have any effect at all. This project will build on the successful proof-of-concept from Phase I that demonstrated the platform's ability to identify directly functional antibody agonists for a human GPCR. The proposal addresses the four main technical requirements that pharmaceutical customers cite as important: Ability to work on many types of GPCRs, ability to isolate antibodies with varied modulating effects, use of a highly diverse, high-quality scFv library, and a workflow that can quickly isolate, optimize and characterize dozens of candidates. The goals of this project are to improve how the platform's yeasts express GPCRs and functionally couple them to different selectable readouts, construct a proprietary scFv library, and optimize the workflow by incorporating sequencing bioinformatics and antibody characterization, including flow cytometric analysis of cell-binding and functional assays on cultured mammalian cells. 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.