Discovery and Optimization of Neutralizing SARS-CoV-2 Antibodies Using ALTHEA Gold Plus Libraries™

We recently reported the isolation and characterization of anti-SARS-CoV-2 antibodies from a phage display library built with the VH repertoire of a convalescent COVID-19 patient, paired with four naive synthetic VL libraries. One of the antibodies, called IgG-A7, neutralized the Wuhan, Delta (B.1.617.2) and Omicron (B.1.1.529) strains in authentic neutralization tests (PRNT). It also protected 100% transgenic mice expressing the human angiotensin-converting enzyme 2 (hACE-2) from SARS-CoV-2 infection. In this study, the four synthetic VL libraries were combined with the semi-synthetic VH repertoire of ALTHEA Gold Libraries (TM) to generate a set of fully naive, general-purpose, libraries called ALTHEA Gold Plus Libraries (TM). Three out of 24 specific clones for the RBD isolated from the libraries, with affinity in the low nanomolar range and sub-optimal in vitro neutralization in PRNT, were affinity optimized via a method called Rapid Affinity Maturation (RAM). The final molecules reached sub-nanomolar neutralization potency, slightly superior to IgG-A7, while the developability profile over the parental molecules was improved. These results demonstrate that general-purpose libraries are a valuable source of potent neutralizing antibodies. Importantly, since general-purpose libraries are ready-to-use, it could expedite isolation of antibodies for rapidly evolving viruses such as SARS-CoV-2.

Automated summary

We isolated and characterized anti-SARS-CoV-2 antibodies from a convalescent COVID-19 patient's VH repertoire, combined with four synthetic VL libraries. One of the antibodies, IgG-A7, showed neutralizing activity against the Wuhan, Delta, and Omicron strains, and protected transgenic mice from SARS-CoV-2 infection. General-purpose libraries, in combination with affinity optimization methods, can provide potent neutralizing antibodies, which is especially important for rapidly evolving viruses like SARS-CoV-2.