Broadly neutralizing antibodies against COVID-19

The COVID-19 pandemic, caused by SARS-CoV-2, has had a devastating global impact, resulting in hundreds of millions of infections and millions of deaths by January 2023 (WHO data). While vaccines have significantly reduced disease severity, and several antiviral drugs (Paxlovid, Veklury) and monoclonal antibodies (mAbs; bebtelovimab, bamlanivimab, etesevimab, sotrovimab, casirivimab and imdevimab, cilgavimab and tixagevimab) have been approved for clinical use, the virus's rapid evolution poses a significant challenge. SARS-CoV-2 has rapidly mutated, generating multiple variants with increased transmissibility and immune evasion capabilities. Many previously effective mAbs, including those approved for therapeutic use, have lost their neutralizing activity against newer variants. This necessitates the development of broadly neutralizing antibodies (bnAbs) to combat current and future variants.

The major antigens of SARS-CoV-2 are the nucleoprotein and the trimeric spike glycoprotein. Numerous studies have characterized spike-binding antibodies as potent neutralizers. The spike protein comprises S1 and S2 subunits, linked by a furin protease cleavage site. S1 mediates ACE2 receptor binding, while S2 facilitates membrane fusion. The S1 subunit contains the NTD, SD1, and RBD, all known to bind neutralizing antibodies. The RBD harbors the ACE2-binding site. Most potent neutralizing mAbs target the RBD and interfere with ACE2 binding. However, mutations in the RBD, often near or within the ACE2-binding site, allow the virus to escape neutralization. The NTD, while also a target for neutralizing antibodies, is less conserved and therefore less suitable for broadly neutralizing antibody development. Less commonly targeted but still relevant are SD1, the stem-helix region, and the fusion peptide.

This review article synthesizes information from published research on broadly neutralizing monoclonal antibodies (mAbs) targeting SARS-CoV-2. The authors analyze the existing literature on mAbs targeting different epitopes on the spike protein, including the receptor-binding domain (RBD), subdomain 1 (SD1), stem helix, and fusion peptide. They examine the structural basis for antibody binding and neutralization, analyzing the impact of viral mutations on antibody efficacy. The review focuses on the characteristics of broadly neutralizing antibodies, discussing their binding sites, neutralization mechanisms, and their potency against various variants of concern (VoCs) and currently circulating strains. The information presented is derived from various peer-reviewed publications, including structural studies (cryo-EM, X-ray crystallography) and functional assays (neutralization assays, animal models). The authors categorize the antibodies based on their target epitopes and discuss their respective strengths and weaknesses in terms of breadth and potency of neutralization.

The review identifies several broadly neutralizing mAbs with varying degrees of potency and breadth of neutralization. Those targeting the RBD near the neck and shoulders generally show the strongest neutralizing abilities, directly blocking ACE2 binding. However, most of these have been rendered ineffective by mutations in emerging variants. A few RBD-targeting mAbs retain activity against multiple variants, including Alpha, Beta, Gamma, Delta, BA.1, BA.2, and BA.4/5, but even these may lose effectiveness against newer sublineages due to mutations such as R346X, K444X, V445X, N450D, and N460X. Omi-42, a particularly noteworthy mAb, retains potent neutralizing ability against all variants tested to date, likely due to its overlapping footprint with ACE2. Antibodies binding to more conserved regions on the RBD's left flank or back, while less potent, show broader neutralizing ability. MAbs targeting SD1, the stem helix, or the fusion peptide display broader neutralization but are generally less potent. These less potent antibodies could be used in cocktails with more potent mAbs, or bispecific antibodies could be developed combining these.

The rapid evolution of SARS-CoV-2, driven by mutations within antibody-binding epitopes, underscores the need for broadly neutralizing antibodies. The emergence of the Omicron BA.1 variant highlighted the widespread escape from pre-existing immunity. The subsequent evolution of Omicron subvariants reveals continued immune escape. While some RBD-targeting antibodies retain activity against various variants, this study shows the limitations of relying on single-epitope targeting. The observation that antibodies targeting more conserved regions on the RBD or other functionally important regions (SD1, stem helix, fusion peptide) show broader neutralizing capabilities, though weaker, supports the development of antibody cocktails and bispecific antibodies. Further research is needed to enhance the potency of these broadly neutralizing antibodies.

The study demonstrates that broadly neutralizing antibodies targeting various conserved regions on the SARS-CoV-2 spike protein offer a potential strategy for combating viral evolution. While some antibodies exhibit potent but narrow neutralization, others offer broader but weaker neutralization. Combining these through cocktails or bispecific antibodies could enhance overall efficacy and reduce the likelihood of escape variants. Future research should focus on engineering improved bnAbs, exploring novel epitopes, and optimizing antibody cocktails for improved potency and breadth of neutralization.

This review is limited by the rapidly evolving nature of SARS-CoV-2. New variants continue to emerge, potentially rendering even the most broadly neutralizing antibodies ineffective. The review relies on existing literature and may not encompass all relevant research. Further, while the mechanisms of action are discussed, precise details of neutralization mechanisms for all mentioned antibodies might require further investigation.