Researchers have characterized a large set of therapeutic antibodies against the SARS-CoV-2 mutant

A-Alpha Bio in the United States. A team of scientists recently conducted a large-scale screening of 33 therapeutic antibodies to determine their binding affinity for a number of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. It was. The team analyzed the effect of potential mutations in the spike receptor binding domain (RBD) on antibody efficacy. Research is currently bioRxiv* Preprint server.

Background

Therapeutic monoclonal antibodies developed against SARS-CoV-2 are highly effective in reducing the severity and mortality of coronavirus disease 2019 (COVID-19) in both clinical trials and real-world pandemic situations. Is shown. Some antibody candidates are currently in Phase 2 and 3 clinical trials, and some have already received emergency use authorization from health authorities around the world.

Most therapeutic antibodies are designed to target the SARS-CoV-2 spike RBD, which can interfere with the interaction of RBD with host cell angiotensin converting enzyme 2 (ACE2). I will. Therefore, it is clear that mutations that occur in spike RBD can alter RBD binding. Effectiveness of antibody. In this regard, studies have shown that newly emerging SARS-CoV-2 mutants with spiked RBD mutations can avoid antibody-mediated neutralization.

the study

In the current study, scientists examined the binding affinity of 33 therapeutic antibody candidates for a large panel of SARS-CoV-2 mutants. Among the antibodies tested are nine clinically relevant antibodies, including Imdevimab, Casilivimab, and Bamlanivimab.

The AlphaSeq assay was used to evaluate over 150,000 protein-protein interactions between antibodies and most single amino acid substitution mutations present in spike RBD. The analysis also included a large number of predominantly circulating SARS-CoV-2 mutants with multiple spike mutations.

In addition, they analyzed protein-protein interactions to identify the major epitopes of each antibody and detected mutations responsible for the loss of epitope binding capacity of each antibody.

Important findings

First, scientists screened all tested antibodies against a site-saturated mutagenesis library containing approximately 75% of all single-amino acid variants at 165 sites within the spike RBD. They identified a number of RBD sites with different patterns of mutation susceptibility among antibodies. This observation emphasizes the diversity of epitopes between antibodies.

They analyzed each of these RBD sites to identify antibody-specific epitopes. Their analysis revealed that about 21 antibodies have putative epitope residues. They validated the findings using the known structure of the antibody-RBD complex.

In addition, they examined the binding of ACE2 to all tested antibodies against a panel of 34 spiked RBD mutants, including single, double, and triple mutations. The panel also included five recently emerged variant strains of concern (B.1.1.7, B.1.351, P.1, B.1.427, and B.1.429) and four associated coronavirus RBDs. ..

Analysis revealed that all five of concern had significantly increased ACE2-binding affinity. For antibodies, extensive binding to the tested RBD variant was observed.

Scientists have specifically analyzed the efficiencies of nine clinically relevant antibodies and found no significant variation in the binding affinity of imdebimab, casilibimab, or bablanivimab for the B.1.1.7 mutant. It was. However, they detected a decrease in the binding affinity of Kasilibimab and Bamuranibimab for B.1.351 and P.1 mutants. Similar reductions in binding affinity observed with regdanbimab and COR-101 and tixagebimab were found in B.1.1.7, B.1.351, and P.1 and B.1.351, and P.1 variants, respectively. It was.

With respect to cross-reactivity, they found that imdebimab, gamlanivimab, legdanbimab, tixagebimab, sirgabimab, and COR-101 were highly specific for SARS-CoV-2 spike RBD, while kacilibimab, sotrobimab, and etesebimab differed. It was observed to show cross-reactivity. Related RBD Coronavirus, SARS-CoV-1, LYRa11, WIV1, RaTG13, etc.

Significance of research

This study provides a detailed overview of the epitope specificity and binding affinity of 33 therapeutic antibodies targeting the SARS-CoV-2 spike RBD. In addition, this study characterizes the binding affinity of clinically relevant antibodies to emerging and concerned mutant strains and highlights the effect of RBD mutations on antibody efficacy.

*Important Notices

bioRxiv publishes unpeer-reviewed preliminary scientific reports and should not be considered definitive, guide clinical / health-related behaviors, or be treated as established information.