Powerful neutralizing antibody against SARS-CoV-2 variants of concern

The coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been accurately referred to as the most devastating outbreak of this century. The initial hope that the rapidly developed vaccines would help terminate the massive threat posed by SARS-CoV-2 to human life, health, social and economic well-being waned in the face of the emergence of multiple viral variants that were more transmissible and/or capable of resisting neutralization by antibodies elicited by earlier strains.

A new paper published in the journal Cell Reports discusses a new antibody with potent neutralizing activity against the ancestral SARS-CoV-2 strain, as well as newer variants of SARS-CoV-2, rekindling hope that it could be used to prevent COVID-19.

Study: A Highly Potent Antibody Effective Against SARS-Cov-2 Variants of Concern. Image Credit: Kateryna Kon / Shutterstock.com

Background

Intensive research and unprecedented financial investment have been devoted to the development of effective and safe antivirals and/or monoclonal antibodies. These efforts have subsequently led to the marketing of better tests for diagnosis of the infection, surveillance using specific antibodies, vaccines with high rates of efficacy against SARS-CoV-2, as well as the identification of some specific therapies that have proved useful including neutralizing monoclonal antibodies.

Several SARS-CoV-2 variants of concern (VOCs) have emerged since late 2020, including the Alpha, Beta, Gamma, and Delta variants. The first of these was the Alpha, with 65% to 75% higher transmissibility as compared to the then-dominant D614G lineage. This SARS-CoV-2 variant rapidly rose to global dominance.

Subsequently, the Beta and Gamma variants were then identified, both of which have common mutations including a triple substitution in the receptor-binding domain (RBD) of the viral spike protein. These mutations lead to higher RBD affinity for the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell, as well as RBD evasion of antibody recognition.

These VOCs have driven successive resurgences of SARS-CoV-2, as well as reduced the efficacy of neutralizing therapeutic antibodies in COVID-19 patients. Reinfection with SARS-CoV-2 has also become more common.

Moreover, although billions of vaccine doses have been rolled out already, some people are immunocompromised and unable to respond with an effective immune response to the vaccine.

The current study examines the role of a powerful and broad-spectrum monoclonal antibody against SARS-CoV-2 in treating severely ill COVID-19 patients, as well as providing passive immunity in immunocompromised individuals.

Study findings

The researchers of the current study identified the antibody, which they termed P5C3, from convalescent plasma samples obtained from eight individuals who had recovered from COVID-19. They represented part of a cohort of 40 hospitalized COVID-19 patients with anti-spike antibodies. These eight had the highest three-month titers of anti-spike immunoglobulin (Ig)G antibodies.

The plasmablasts and memory B-cell clones with the highest spike binding activity were chosen to express the monoclonal antibody (mAb). The ten mAbs that showed the greatest affinity to the spike trimer, with half-maximal effective concentration (EC50) values of 0.012–0.120 μg/mL, were studied further for binding to VOC spike antigens.

The benchmark used was three mAbs in clinical use, of which included REGN1033, REGN10987, and S309. The spike mutations tested for binding included N439K, S477N, and E484K, all of which are found in the Beta and Gamma lineages. Additionally, the L452R mutation of the Delta variant, as well as the full set of mutations characterizing the Alpha, Beta and Gamma VOCs, were also evaluated.

The mAb P5C3 had the highest binding affinity, without loss relative to the ancestral spike protein, for all tested spike variants, with the EC50 being 0.02–0.035 μg/mL. Conversely, the Regeneron mAb REGN10933 showed a drop in binding affinity by 60-fold. Again, this mAb bound the triple substitution K417N/E484K/N501Y of the Beta and Gamma variants with 15-fold and almost 200-fold lower affinity.

As for another Regeneron product REGN10987, the loss of binding was lower for all except for the N493K mutation, which showed a 4.4-fold lower affinity. S309 was another antibody with less binding affinity that was found to be 12-fold less than with P5C3. The other nine mAbs were less potent at binding to the spike variants.

P5C3 competed for the RBD with ACE2 and REGN10933. With REGN10987 and S309, P5C3 inhibited binding by 20% non-competitively.  REGN10987 showed steric hindrance, which is defined as a change in conformation triggered by binding. This led to partial competitive binding with both the others.

With an EC80 value of 0.021 μg/mL, P5C3 was the most potent neutralizing antibody against all tested spike variants, showing equivalent neutralization for all except S477N. Even with this, the EC50 was 0.08 μg/mL. In contrast, REGN10933 was two-fold less active at neutralizing the ancestral strain but showed a marked increase in EC50 when the spike variant contained E484K, a mutation found in the Beta, Gamma, and Lambda variants.

This pattern was found with REGN10987, which was also less potent than P5C3 by 7-10-fold against E484K mutation. It did not show significant activity against particles with a spike containing N493K.

When compared to the benchmark mAbs, P5C3 had low EC50 values against all tested mAbs, at 0.011 μg/mL. However, REGN10933, REGN10987, and S309 all showed lower potency against the B.1.351 and mink variants, all the while remaining unaltered against the D614G and Alpha variants.

REGN10987 and S309 both displayed broad neutralization potential against these variants, but EC80 values of REGN10987 were 5.6- to 9.5-fold less potent than measured for P5C3 LS against the 2019-nCoV and D614G viruses, and S309 was 28- to 177-fold less potent against all tested viruses.”

The scientists also explored the P5C3 paratope-trimeric spike interaction. The target epitope in this case overlapped the receptor-binding domain (RBD) of the spike.

Thus, P5C3 is a class I neutralizing antibody that is able to bind the RBD only when in an open conformation. The target epitope is large, with a 600 Å2 surface extending around F486, overlapping 23 residues of the P5C3 and 21 of the spike RBD. This accounts for its strong affinity and potency.

The P5C3 uses five complementarity-determining regions (CDRs); namely, CDRs H1, H2, and H3 of the heavy chain, as well as L1 and L3 of the light chain, to bind the RBD. However, this is an unusual mode of binding and is due to the large separation of two CDR regions in space.

The mAb epitope has a large buried surface area that spans 600 Å2. Occupying such a large area without specific crucial binding sites, this domain should escape resistance mutations. In fact, even mutations such as K417N or E484K, which overlap the margin of the binding epitope of P5C3, are still susceptible to neutralization.

Its binding modes involve some of the strands of the spike protein, interactions with the ACE2 receptor, and hydrophobic contacts with the RBD core. This indicates that the virus cannot readily evolve escape mutations to P5C3 without compromising its antigenic integrity by faulty protein folding or losing binding affinity for the ACE2 receptor.

The antibody interacts with ACE2 at a site that overlaps most of the mutations found in the spike variants, centered on F486 on the RBD. The fact that P5C3 overlaps or interacts, individually or in clusters, with 21 spike antigens allows it to overcome affinity losses occurring as a result of localized mutations. Mutations at this epitope thus actually exert a cost in terms of severely compromised viral fitness.

This mAb was found to protect against infection with SARS-CoV-2 in a hamster model when given prophylactically. Viral RNA levels were lower by 4 logs in treated animal lung tissue as compared to controls.

At all but the lowest dose, the infectious virus could not be detected in lung tissue in any animal. Furthermore, even at the lowest dose, four of seven animals had an undetectable infectious virus, whereas the others had a 2-log lower viral particle count.

Implications

P5C3 is a potent neutralizing mAb that interacts with the open RBD to block ACE2 binding. Unlike other class I antibodies in current clinical use, it retains inhibitory activity against all spike variants in circulation.

It is predicted that direct mutations in the RBD at the contact site with P5C3 will invariably impact the affinity for ACE2, resulting in a reduced overall infectivity and fitness of the virus.”

The excellent protection against SARS-CoV-2 infection in treated hamsters further extends the in vitro neutralization results. Moreover, P5C3 does not compete for ACE2 binding with other neutralizing antibodies, which means they can be used as a cocktail to enhance neutralizing activity and prevent the emergence of escape mutations.

The researchers also suggest that P5C3 may be part of a public antibody family, sharing the VH1-58 allele. Overall, this antibody offers a therapeutic option for immunocompromised individuals who can be protected by administration two or three times a year.

With its potent neutralizing properties against all Spike mutations and SARS-CoV-2 variants identified so far and the demonstrated in vivo prophylactic protection in the hamster challenge model, P5C3 represents a best-in-class anti-SARS-CoV-2 antibody for use in the prophylactic setting.”

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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