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

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February 27, 2023

Authors

Omar U. Guzmán-Bringas^1,2, Keyla M. Gómez-Castellano^1,2, Edith González-González^1,2, Juana Salinas-Trujano^1,2, Said Vázquez-Leyva^1,2, Luis Vallejo-Castillo^1,2, Sonia M. Pérez-Tapia^1,2,3, and Juan C. Almagro^1,4

Organizations

Unidad de Desarrollo e Investigación en Bioterapéuticos (UDIBI), Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala S/N, Colonia Santo Tomás, Alcaldía Miguel Hidalgo, Mexico City 11340, Mexico
Laboratorio Nacional Para Servicios Especializados de Investigación, Desarrollo e Innovación (I + D + I) Para Farmoquímicos y Biotecnológicos, LANSEIDI-FarBiotec-CONACyT, Prolongación de Carpio y Plan de Ayala S/N, Colonia Santo Tomás, Alcaldía Miguel Hidalgo, Mexico City 11340, Mexico
Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala S/N, Colonia Santo Tomás, Alcaldía Miguel Hidalgo, Mexico City 11340, Mexico
Department of Health Sciences and Technology, ETH Zürich, 8092 Zürich, Switzerland
GlobalBio, Inc., 320 Concord Ave, Cambridge, MA 02138, USA

Abstract

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 naïve 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™ to generate a set of fully naïve, general-purpose, libraries called ALTHEA Gold Plus Libraries™. 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.