SBIR Phase I: Stable prophylactic antibodies

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The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase I project is to solve a variety of infectious diseases for which there is no adequate prevention or therapy, such as HIV, flu, malaria, and the common cold. Vaccination has proven immensely difficult for these diseases, often because there are countless natural strains. Providing antibodies directly represents a possible solution because some of the broadest antibodies can subdue 97% or more of circulating strains. However, antibodies will not last beyond a few months in the body. This project proposes to make a collection of mutations in the constant part of antibodies to stabilize them potentially for decades or even a lifetime. This will improve public health.This Small Business Innovation Research (SBIR) Phase I project will advance the potential applications of mutagenizing the Fc region of a model antibody toward the eventual development of stable prophylactic antibodies. First, the Fc will be made resistant to all cellular and all major microbial antibody proteases. Mutations conferring resistance of antibodies to some proteases have already been achieved; these will be combined in the model system. Resistance to all remaining proteases will be engineered by targeted mutation, if the cleavage sites are known, and by comprehensive mutation, if the cleavage sites are unknown. High-throughput screening of mutants will be facilitated by full-length Immunoglobulin G phage display. Second, Fc is stabilized in vivo by the neonatal Fc receptor (FcRn). An unbiased screen of all possible single and double mutants in Fc, also by full-length Immunoglobulin G phage display, will isolate mutants that have still further enhanced binding to FcRn.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.