SBIR Phase I:Combinatorial Platform for the Discovery of Improved Molecular Recognition Components for Use in Therapeutic and Diagnostic Antibodies

The broader impact of this Small Business Innovation Research (SBIR) Phase I project is the fundamental improvement of crucial antibody components that recognize and bind therapeutic or diagnostic targets. Modern antibodies are usually engineered as protein chimeras comprised of different parts, including one to several molecular recognition domains that mediate binding. The proposed research will integrate breakthroughs in next generation DNA sequencing and synthetic and computational biology to create a combinatorial high throughput platform for generating better recognition domains. The core aim is to creatively and efficiently use genetic information from patients, pathogens and antibodies for the advancement of therapeutics and diagnostics across a spectrum of diseases. The platform could expedite the design and discovery of current antibody-based therapeutics to reduce the enormous costs and time required to bring these drugs to market. The platform is ideally suited for the development of new classes of therapeutics where very rapid, adaptable and inexpensive response is required, such as in truly personalized treatments of continuously changing tumors or in rapidly evolving viral pandemics where passive vaccines need to be generated at scale. The proposed project will demonstrate that a novel yeast-based high throughput screening platform is able to efficiently generate molecular recognition domains that specifically recognize clinically important targets. The proof-of-concept target antigens are a human receptor/ligand pair important for the immunosuppression of certain cancers and a coronavirus surface protein that mediates infection by binding a human receptor. In these screens, the use of yeast cells that surface display antibody recognition domains, and secrete these target antigens from the same cell, enables next generation sequencing to identify the genetic information encoding both the domain and the target. This dual detection capability is made possible by innovative fluorescent biosensors and is unique to this screening platform. The project will utilize synthetic biology to construct a library with a rich variety of recognition domains that will be screened simultaneously against several target antigens of varying design. Next generation sequencing analysis will show that it is practical to implement combinatorial screens using engineered recognition domains and antigens to identify recognition domains with desired binding specificity and affinity. 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.