Potent SARS-CoV-2 neutralizing antibodies selected from a human antibody library constructed decades ago

Abstract

Combinatorial antibody libraries not only effectively reduce antibody discovery to a numbers game, but enable documentation of the history of antibody responses in an individual. The SARS-CoV-2 pandemic has prompted a wider application of this technology to meet the public health challenge of pandemic threats in the modern era. Herein, we used a combinatorial human antibody library constructed 20 years before the COVID-19 pandemic to discover three highly potent antibodies that selectively bind SARS-CoV-2 spike protein and neutralize authentic SARS-CoV-2 virus. Compared to neutralizing antibodies from COVID-19 patients with generally low somatic hypermutation (SHM), these antibodies contain over 13-22 SHMs, many of which are involved in specific interactions in crystal structures with SARS-CoV-2 spike RBD. The identification of these somatically mutated antibodies in a pre-pandemic library raises intriguing questions about the origin and evolution of human immune responses to SARS-CoV-2.

Microfluidic Affinity Profiling reveals a Broad Range of Target Affinities for Anti-SARS-CoV-2 Antibodies in Plasma of COVID-19 Survivors

“…3d ). This is consistent with previous findings of affinity maturation, which normally occurs after the second exposure to the pathogen 31–33 , and is further supported by the finding that many SARS-CoV-2 antibodies have germline sequences without hyper-affinity maturation in germinal centres 34–36 .…”

Neutralizing antibodies targeting SARS-CoV-2 spike protein

“…The low-affinity antibodies or poorly neutralizing antibodies which might be produced after vaccine injection should also be considered during vaccine design. Other efforts to diminish ADE is to introduce LALA mutation in the Fc part of IgG1 ( Renn et al, 2020 ) or adopt the IgG4 format ( Qiang et al, 2020 ) for neutralizing antibodies development. Nanobodies or antibodies in Fab format with no Fc part have the natural advantage of avoiding ADE.…”

“…Antibody library in various types such as single chain (scFv) antibody library, single domain antibody library, Fab antibody library, etc. were employed for selection ( Qiang et al, 2020 , Wang et al, 2020 ) when competition screen with ACE2 was a common selection strategy adopted ( Zeng et al, 2020 ).…”

“…In contrast to the antibodies from convalescent patient, in our lab, three potent SARS-CoV-2 neutralizing antibodies were screened from a combinatorial naïve library established 20 years ago. Furthermore, a high level of somatic hypermutation (up to 15 amino acids per molecule) was found for all three antibodies, many of which are involved in specific interactions revealed by crystal structures with SARS-CoV-2 spike RBD ( Qiang et al, 2020 ).…”

Antibody Libraries as Tools to Discover Functional Antibodies and Receptor Pleiotropism

“…COVID-19 is the biggest global health threat in many generations. Recently it has been reported that a combinatorial human antibody library, constructed 20 years before the current COVID-19 pandemic, was used to select three highly potent antibodies that specifically bind the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, and neutralize authentic SARS-CoV-2 virus [ 67 ]. This suggests that immunological memory after infection with seasonal human coronaviruses may potentially contribute to cross-protection against SARS-CoV-2 [ 68 , 69 ].…”