SBIR Phase I: 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) project is to enable the discovery of needed antibody therapeutics in diseases for which there are no available treatments. These therapies act by increasing or decreasing the activity of a type of cell signaling receptor, "G protein-coupled receptors" (GPCRs). Antibodies are highly specific for their targets, an important characteristic for GPCR drugs, as GPCRs comprise a large family of structurally similar proteins. In fact, small molecule drugs for GPCRs often are toxic due to side effects from acting on structurally similar but functionally unrelated GPCRs. This project will develop the first technology that directly identifies antibodies by their ability to modulate GPCR function. These antibodies will impact society's health by treating currently incurable diseases, and strongly impact scientific understanding by enabling the study of GPCR-related mammalian physiology and disease. The commercial impacts are potentially very large. The global GPCR drug market is over $100B, and over half of marketed antibody therapeutics have annual sales of over $1B. The platform described here has the potential to develop many GPCR antibody therapeutics, and thereby generate an enormous amount of value for patients, society at large, and co-development partners. This SBIR Phase I project proposes to develop a platform for discovering GPCR-modulating antibodies. This platform could be critical for generating tools for studying GPCR-related biology and disease, and for developing therapeutics with fewer side effects than small molecule drugs to treat GPCR-related diseases. Developing functional GPCR antibodies using traditional methods is encumbered by the difficulty in producing antigens that represent the GPCR in a functional state, and a lack of high-throughput assays of GPCR function. The proposed platform and method expresses human GPCRs in Saccharomyces cerevisiae yeast, couples activity to selectable phenotypes, and directly selects antibodies that modulate GPCR function in the same cells. The first objective aims to further characterize the activity and specificity of camelid antibodies ("nanobodies") antagonists that inhibit the endogenous yeast GPCR, Ste2, and then perform agonist selections to identify at least one Ste2 agonist. The second objective aims to further develop the platform to enable interrogating a broader array of human GPCR targets using ScFv antibody libraries, and to identify at least one agonist or antagonist of a therapeutically relevant human GPCR. Positive results will demonstrate the feasibility of the platform.