Rational Design of Antibodies: From Mechanisms of Specificity to Novel Vaccine Strategies

Abstract

Human antibodies are critical for eradication of viral and bacterial infections, while providing the basis for immunological memory. Antibody design using the molecular modeling suite Rosetta is used to answer questions about the molecular basis for antibody polyspecificty as a function of sequence maturation. Germline antibody sequences were found to be the molecular basis for polyspecificity as they can adopt the multiple conformations needed to bind a seemingly infinite antigen structural space. Mature sequences by contrast, are optimized for specificity against one antigen. Antibody design using Rosetta was extended to interrogate the antibody structural repertoire of HIV-naive donor patients to search for patterns that may mimic PG9, a broadly neutralizing antibody against HIV. Broadly neutralizing antibodies against HIV were thought to be the result of years of chronic infection and selective pressure. However, several antibodies were found with modest neutralization potency against HIV indicating that neutralizing antibodies may be prevalent in the HIV-naive donor repertoire. This finding has several implications for new vaccine strategies. Finally, Rosetta was used for the redesign of contemporary antibodies against HIV to investigate whether the immune system has fully optimized broadly neutralizing antibodies for maximum potency and breadth. Antibody design was able to find mutations that increase potency and breadth against HIV.