SBIR Phase II: Stable Prophylactic Antibodies

About This Grant

The broader impact of this Small Business Innovation Research (SBIR) Phase II project is to address infectious diseases for which there is no existing or no adequate vaccine, such as influenza (the flu), malaria, tuberculosis, HIV, and the common cold. The initial effort will address the flu. Antibodies are often given as therapy but are not stable enough to be used as prophylactics. This project aims to discover mutations in a generic antibody that significantly enhances its stability, extending its lifespan from weeks to years. If this stability is achieved then these stable prophylactic antibodies (spAbs) could be given at birth or to adults and would only require re-administration once or twice a decade, or potentially never again. These mutations will be uncovered in a screen, where a library of millions of different mutants is infused and blood is collected at intervals; mutants that confer greater stability will be enriched relative to all other antibodies. These results will contribute to the understanding of antibody structure and can serve as reagents for antibody studies. This project should result in a spAb backbone which can be used as a long-term prophylactic for influenza initially, and other diverse infectious diseases. The proposed project aims to extend known mutations that increase antibody stability to new mutations that significantly increase antibody stability still further such that the resultant spAbs can be given as long-term prophylactics. Work done in the Phase I SBIR has identified a mutation combination that makes the antibody resistant to numerous enzymes that degrade antibodies; is able to bind the stabilizing molecule, the neonatal Fc receptor, better; and maintains the important functions of antibodies in immunity. However, the stability of this mutant combination, while likely greatly extended in vivo, is still short of the necessary stability for use as a long-term prophylactic. Thus, an non-human primate (NHP) screen is proposed. Combining administration of a diverse antibody mutant library with next-generation protein sequencing should uncover mutants that overcome one or more of the many processes and spaces where antibodies are lost in vivo, such as excretion through the urine or loss in the gut. Three successive rounds of mutation will be done in NHPs, each building upon the last. The end result should be an spAb backbone that confers greatly increased stability in the circulation, which can be used to combat numerous infectious diseases, the first application of which is influenza. 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.