Researchers discovered three antibodies that neutralize SARS-CoV-2 virus


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 severe acute respiratory syndrome coronavirus 2 (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, a combinatorial human antibody library constructed 20 years before the coronavirus disease 2019 (COVID-19) pandemic is used 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 three antibodies contain over 13–22 SHMs, many of which are involved in specific interactions in their crystal structures with SARS-CoV-2 spike receptor binding domain.

The identification of these somatically mutated antibodies in a pre-pandemic library raises intriguing questions about the origin and evolution of these antibodies with respect to their reactivity with SARS-CoV-2.

The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus and cause of the coronavirus disease 2019 (COVID-19), poses an unprecedented health crisis and was declared a pandemic by the World Health Organization on March 11, 2020.[1]

As of September 10, 2021, over 222 million individuals have been infected with over 4.5 million deaths ( with several vaccines or specific antiviral drugs approved.

Monoclonal antibodies (mAbs) targeting the viral spike glycoprotein (S) have been shown to have excellent neutralization efficacy in previous treatment of SARS, middle east respiratory syndrome (MERS), and Ebola virus infections as well as in treatment of COVID-19 as shown by recent clinical data,[2] and therefore are of particular interest to combat the current pandemic.[3]

Since the COVID-19 outbreak, the spike glycoprotein has been the main target for development of therapeutic mAbs.[4] Most neutralizing antibodies (NAbs) bind to the receptor binding domain (RBD) of the S protein,[5] although some also bind to the N-terminal domain.[6]

NAbs have been derived from multiple sources, including memory B cells from SARS-CoV-2 convalescent patients,[3, 6, 7] SARS patients,[8] immunized humanized mice that encode the human immunoglobulin repertoire,[9] alpaca nanobodies,[10] single domain human antibodies from a pre-established library,[11] and phage display antibody libraries.[4, 12]

Antibody generation is an evolutionary process of mutation and selection from the B cell repertoire. The combinatorial antibody library technology allows the same evolutionary process to be performed in vitro as it restores the “fossil record” of an individual’s antibody response in a test tube.[13]

Random coupling of variable heavy chain (VH) and variable light chain (VL) sequences in single-chain fragment variable (scFv) libraries greatly expands diversity, thereby allowing for selection of novel antibodies with high binding affinity and neutralization efficacy.[14]

Here, we report the selection and characterization of three potent SARS-CoV-2 antibodies, S-E6, S-B8, and S-D4, from a pre-pandemic naïve human combinatorial antibody library established in 1999 that target the spike RBD and compete with human angiotensin-converting enzyme 2 (hACE2) receptor.[15]

This study provides further evidence that a combinatorial antibody library with an unprecedented diversity can mimic the selection process of natural immunity, permit detection of unexpected, high affinity spike-targeting antibodies with higher somatic hypermutation (SHM), and allow for selection of binding molecules with chemistries beyond those accessible during in vivo selection.

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