Specificity is one of the most important and challenging drug-like properties to optimize during antibody generation and affinity maturation. We have sought to develop methods for designing libraries that maximize antibody specificity in addition to antibody affinity and stability by combining three key advances. First, we have developed a library design method that samples a subset of residues at each position within antibody binding loops based on i) chemical descriptors of antibody specificity and ii) site-specific constraints based on the amino acid diversity observed for antibodies generated by the natural immune system. Second, we have generated antibody libraries with amino acid diversity in the variable region frameworks in addition to the binding loops using &gt;20 different human antibody frameworks that have been validated for high specificity yet are diverse in terms of their variable region sequences and physicochemical properties. Third, we have developed a novel approach for displaying antibody fragments in the Fab format using yeast surface display. We are currently applying using these combined library design and display methods for isolating antibody variants with high specificity against different soluble and aggregated target antigens associated with Alzheimer’s disease. We expect that our methods will improve the rapid and reliable isolation of high-affinity antibodies with drug-like properties.  <br/>

Design and evaluation of novel antibody libraries with drug-like specificity

2019 Spring National Meeting

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