UCSF

Antibodies and antibody-like molecules are broadly used as biochemical reagents and therapeutics. They are highly valued as probes that can distinguish between protein targets with extraordinary molecular detail. A deep understanding of natural antibody structure and function has enabled the development of fully synthetic human antibody libraries for in vitro display. These synthetic libraries recapitulate the sophistication of molecular recognition in antibody complementarity determining regions (CDRs) and in vitro display permits exquisite control over selection conditions. Thus, protein engineers can tailor-make antibodies to bind challenging and non-conventional targets.Here, we describe three examples of protein engineering that leverage synthetic antibody libraries and in vitro display technologies to generate binders to novel epitopes. In Chapter 1, we utilize recombinant antibody pairs to target the post-translational modification (PTM) phosphotyrosine (pY) in folded protein epitopes. In Chapter 2, we develop and deploy a single-domain antibody (sdAb) library to rapidly identify inhibitors to SARS-CoV-2 viral entry. In Chapter 3, we utilize chemo-epitope specific sdAbs to create small-molecule-dependent switches and further engineer them to control cellular therapies.