Sbir phase i: stable prophylactic antibodies

This National Science Foundation Project Grant of $255,927 awarded to Invvax, Inc. on March 1, 2022 seeks to develop stable prophylactic antibodies through February 2023. Funded through the NSF Engineering Directorate's CFDA 47.041 program, this Small Business Innovation Research Phase I project will engineer mutations to antibody Fc regions to resist degradation and enhance binding to the neonatal Fc receptor for potentially decades-long duration. Specifically, the awardee will combine known protease-resistant mutations and conduct unbiased screens to identify additional single and double mutations conferring further resistance to cellular and microbial proteases as well as enhanced FcRn binding. This work advances the potential for stable prophylactic antibodies to address infectious diseases lacking prevention or treatment options such as HIV, influenza, malaria and the common cold.

Abstract

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.