The design of superior biologic therapeutics, including antibodies and engineered proteins, involves optimizing their ability to bind to disease-related molecular targets. Virtual affinity maturation has the potential to quickly focus on the critical hotspot residues without the combinatorial explosion problem of conventional display and library approaches. To achieve this potential, ADAPT (Assisted Design of Antibody and Protein Therapeutics) has been developed as a platform to aid in the selection of mutants that improve/modulate the affinity of antibodies and other biologics. Starting from the crystal structure of an antibody-antigen complex, ADAPT uses a consensus-based protocol which interleaves computational predictions with experimental validation. Multiple rounds of optimization yield mutants with significant increases in binding affinity. The ADAPT protocol significantly enhances the robustness of the design and selection of mutants. Initially the ADAPT computational protocol was validated using a curated antibody-antigen structure-function data set (SiPMAB), demonstrating the power of using a consensus-based protocol. ADAPT was applied to three antibody Fab-antigen systems with over 90% of designed and experimentally validated mutants having higher affinities than the parent. ADAPT was then applied on a single-domain antibody, leading to a 10-fold affinity improvement.

Recent advances in affinity maturation with the assisted design of antibody and protein therapeutics (ADAPT) platform

255th National Meeting (2018)

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