Potent Molecular Feature-based Neutralizing Monoclonal Antibodies as Promising Therapeutics Against SARS-CoV-2 Infection

Abstract

The 2019–2020 winter was marked by the emergence of a new coronavirus (SARS-CoV-2) related disease (COVID-19), which started in Wuhan, China. Its high human-to-human transmission ability led to a worldwide spread within few weeks and has caused substantial human loss. Mechanical antiviral control approach, drug repositioning, and use of COVID-19 convalescent plasmas (CPs) were the first line strategies utilized to mitigate the viral spread, yet insufficient. The urgent need to contain this deadly pandemic has led searchers and pharmaceutical companies to develop vaccines. However, not all vaccines manufactured are safe. Besides, an alternative and effective treatment option for such an infectious disease would include pure anti-viral neutralizing monoclonal antibodies (NmAbs), which can block the virus at specific molecular targets from entering cells by inhibiting virus-cell structural complex formation, with more safety and efficiency than the CP. Indeed, there is a lot of molecular evidence about the protector effect and the use of molecular feature-based NmAbs as promising therapeutics to contain COVID-19. Thus, from the scientific publication database screening, we here retrieved antibody-related papers and summarized the repertory of characterized NmAbs against SARS-CoV-2, their molecular neutralization mechanisms, and their immunotherapeutic pros and cons. About 500 anti-SARS-CoV-2 NmAbs, characterized through competitive binding assays and neutralization efficacy, were reported at the writing time (January 2021). All NmAbs bind respectively to SARS-CoV-2 S and exhibit high molecular neutralizing effects against wild-type and/or pseudotyped virus. Overall, we defined six NmAb groups blocking SARS-CoV-2 through different molecular neutralization mechanisms, from which five potential neutralization sites on SARS-CoV-2 S protein are described. Therefore, more efforts are needed to develop NmAbs-based cocktails to mitigate COVID-19.

Passive Immunotherapy Against SARS-CoV-2: From Plasma-Based Therapy to Single Potent Antibodies in the Race to Stay Ahead of the Variants

“…Both of these bispecific antibodies exhibited higher therapeutic efficacy than the equivalent cocktail of CoV-14 and CoV-06 antibodies [ 244 ], indicating the potential power of combining antibodies into a single molecule over using cocktails of multiple antibodies [ 331 ]. As might be expected from previous work [ 321 ], the tetravalent IgG-(scFv) 2 bispecific antibody comprised of CoV-14 and CoV-06 was superior to the CrossMAb format as well as the two-antibody cocktail in SARS-CoV-2 neutralization activity in vitro, including broad neutralization of escape variants, and enhanced protective efficacy in vivo [ 331 ]. This is one example of the principle, described throughout this work, that an increase in antibody valency correlates with an increased ability to neutralize SARS-CoV-2 [ 332 , 333 ].…”

“…Although hundreds of potent nAbs have been successfully isolated (cf., [ 290 , 321 ]), studies on antibody resistance have demonstrated that rapid viral escape arises with any monotherapy regardless of antibody neutralizing activity and epitope conservation [ 322 – 324 ]. Thus, many researchers and companies have turned to a rational combination of at least two neutralizing antibodies that possess different, non-overlapping epitopes together as a combination therapeutic to provide broader epitope coverage, and hopefully, greater resistance against variants that may arise over time [ 211 , 245 , 261 , 325 ].…”

Structure-based neutralizing mechanisms for SARS-CoV-2 antibodies

“…SARS-CoV-2 neutralizing antibodies are derived from COVID-19 convalescent patients, phage display, naïve libraries, or other strategies [ 20 ]. The neutralizing antibodies can be classified into three sets targeting the receptor-binding domain (RBD), the N-terminal domain (NTD), or S2 subunit of SARS-CoV-2 spike (S) glycoprotein [ 20 , 21 ] ( Figure 2 A). RBD-directed neutralizing antibodies can be further divided into six groups (group A-F) [ 22 , 23 ].…”

CD8+ T-cell immune escape by SARS-CoV-2 variants of concern

“…The spike mutation at residue K417 in almost all VOCs, but not the Alpha variant, has been predicted to cause an overwhelmingly disruptive effect, which may make these variants resistant to vaccine-induced humoral immunity ( 3 , 12 ). Overall, at the molecular level, these spike mutations induce molecular tridimensional changes at the antibody binding sites, which become inaccessible for antibodies and therefore impede antibody binding ( 20 , 21 ). Also, the residues changed are such that mutations induce an increased binding affinity (or interaction force) of RBD to angiotensin-converting enzyme 2 (ACE2), like in the cases of mutations V367F, L452Q, N501Y, and D614G, which is associated with increased transmissibility ( 1 , 10 , 11 , 21 – 23 ).…”

“…Overall, at the molecular level, these spike mutations induce molecular tridimensional changes at the antibody binding sites, which become inaccessible for antibodies and therefore impede antibody binding ( 20 , 21 ). Also, the residues changed are such that mutations induce an increased binding affinity (or interaction force) of RBD to angiotensin-converting enzyme 2 (ACE2), like in the cases of mutations V367F, L452Q, N501Y, and D614G, which is associated with increased transmissibility ( 1 , 10 , 11 , 21 – 23 ).…”