Nature: A pandemic-enabled comparison of discovery platforms demonstrates a naïve antibody library can match the best immune-sourced antibodies

Nature Communications 2022 | 13 | Article 462 | 24 JAN 2022

Fortunato Ferrara, M. Frank Erasmus, Sara D’Angelo, Camila Leal-Lopes, André A. Teixeira, Alok Choudhary, William Honnen, David Calianese, Deli Huang, Linghan Peng, James E. Voss, David Nemazee, Dennis R. Burton, Abraham Pinter & Andrew R. M. Bradbury

Abstract

As a result of the SARS-CoV-2 pandemic numerous scientific groups have generated antibodies against a single target: the CoV-2 spike antigen. This has provided an unprecedented opportunity to compare the efficacy of different methods and the specificities and qualities of the antibodies generated by those methods. Generally, the most potent neutralizing antibodies have been generated from convalescent patients and immunized animals, with non-immune phage libraries usually yielding significantly less potent antibodies. Here, we show that it is possible to generate ultra-potent (IC₅₀ < 2 ng/ml) human neutralizing antibodies directly from a unique semisynthetic naïve antibody library format with affinities, developability properties and neutralization activities comparable to the best from hyperimmune sources. This demonstrates that appropriately designed and constructed naïve antibody libraries can effectively compete with immunization to directly provide therapeutic antibodies against a viral pathogen, without the need for immune sources or downstream optimization.

Introduction

As of early November 2021, over 248 million people worldwide have been documented to be infected with SARS-CoV-2, the novel coronavirus causing COVID-19, resulting in over 5 million deaths. This has led to worldwide interest in the rapid development of effective diagnostic, prophylactic, and therapeutic options for this pandemic. Several COVID-19 vaccine candidates have been approved and are being broadly distributed^1,2,3, but it is unlikely the bulk of the world’s population will be vaccinated before 2023, during which time the virus will continue to spread and mutate, risking the development of vaccine-resistant variants. On the therapeutic front, in addition to drug repurposing⁴ there has been intense interest in generating neutralizing antibodies against SARS-CoV-2⁵. Most biotech/pharma companies and academic laboratories with antibody technology have generated antibodies against this virus, concentrating on the spike (S) protein, a homotrimeric glycoprotein anchored in the viral membrane, responsible for binding to angiotensin-converting enzyme-2 (ACE2)⁶, the host cell receptor mediating viral entry.