<br/>Many viruses with pandemic potential rapidly accumulate mutations that have the potential to evade an adaptive immune response by masking or mutating key epitopes recognized by existing antibodies. The identification of broadly neutralizing antibodies (bnAbs), or antibodies that can bind and neutralize multiple subtypes or strains of a virus, is promising in regard to potential prevention and treatment of these viruses. Despite the neutralization breadth, most bnAbs are not very abundant in human sera and typically exist in low titers. A better understanding of antibody development and how bnAbs are elicited could lead to better monoclonal antibody therapies and improved vaccine design. To that end we have developed a technology to evaluate and identify likely developmental antibody pathways in vivo. Our platform involves the following components: (i.) massively parallel mutagenesis to encode all possible combinations between a universally conserved ancestral sequence and a mature bnAb; (ii.) a Fab yeast display screening platform; (iii.) simultaneous evaluation of affinities for all antibody variants in parallel using deep sequencing and maximum likelihood estimation; and (iv.) agent based modeling to recreate likely antibody trajectories. We demonstrate this technology on anti-SARS-CoV-2 neutralizing Abs and anti-Influenza bnAbs.

Influence of evolutionary trajectories on antibody affinity maturation

ACS Spring 2022

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