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/lp/oxford-university-press/perspectives-on-the-development-of-neutralizing-antibodies-against-ISMw3ooWfE
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- Oxford University Press
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- Published by Oxford University Press 2020.
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- 2516-4236
- DOI
- 10.1093/abt/tbaa009
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Abstract
SARS-CoV-2 gains entry to human cells through its spike (S) protein binding to angiotensin-converting enzyme 2 (ACE2). Therefore, the receptor binding domain (RBD) of the S protein is the primary target for neutralizing antibodies. Selection of broad-neutralizing antibodies against SARS-CoV-2 and SARS-CoV is attractive and might be useful for treating not only COVID-19 but also future SARS-related CoV infections. Broad-neutralizing antibodies, such as 47D11, S309, and VHH-72, have been reported to target a conserved region in the RBD of the S1 subunit. The S2 subunit required for viral membrane fusion might be another target. Due to their small size and high stability, single-domain antibodies might have the ability to be administered by an inhaler making them potentially attractive therapeutics for respiratory infections. A cocktail strategy combining two (or more) antibodies that recognize different parts of the viral surface that interact with human cells might be the most effective. Statement of Significance: Neutralizing antibodies are being developed to treat COVID-19 by reducing SARS-CoV-2 infectivity. Broad-neutralizing antibodies targeting a conserved region on the spike proteins of SARS-CoV-2 and SARS-CoV might be useful for treating COVID-19 and future infections. A cocktail strategy combining two or more antibodies might be the most effective. KEYWORDS: SARS-CoV-2; SARS-CoV; COVID-19; neutralizing antibody; spike (S) protein INTRODUCTION animal models [6]. In another report, single domain anti- bodies that bind the spike (S) protein of MERS-CoV and COVID-19 is caused by the new coronavirus SARS-CoV-2 SARS-CoV were isolated from a shark V single domain NAR (initially called 2019-nCoV) [1, 2]. As of May 16, 2020, there antibody phage display library [7]. are 4,632,903 confirmed cases and 311,739 death worldwide with 188 countries affected (https://coronavirus.jhu.edu/ma p.html). It is widely believed that neutralizing antibodies THE ROLE OF THE S PROTEIN IN SARS-CoV-2 can be used to treat COVID-19 by reducing SARS-CoV-2 INFECTION infectivity [3]. In the current issue of Antibody Therapeu- tics, two articles related to COVID-19 have been published As an enveloped single strand RNA virus, SARS-CoV- through a fast track peer review, revision, and production 2 enters into a human cell through its S protein binding [4, 5]. While most publications in our journal have been to angiotensin-converting enzyme 2 (ACE2) [8, 9](Fig. 1). focused on cancer therapies, it was not the first time that After endocytosis of the virus, cell surface ACE2 is down- Antibody Therapeutics published papers that were relevant regulated. Activation of the renin–angiotensin–aldosterone to antibody development for viral diseases. In one previous system may cause lung injury to viral infection [8]. The study, a human papillomavirus vaccine using a novel virus- genome sequence (∼30 kilobases) of SARS-CoV-2 shares like particle was shown to induce antibody response in the highest level of genetic similarity (∼96% identity) with To whom correspondence should be addressed. Dr. Mitchell Ho, Senior Investigator, Laboratory of Molecular Biology and Director, Antibody Engineering Program, Bldg. 37, Room 5002, 37 Convent Drive MSC 4264, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. Web: https://ccr.cancer.gov/mitchell-ho. Email: homi@mail.nih.gov Published by Oxford University Press 2020. This work is written by US Government employees and is in the public domain in the US. 110 Antibody Therapeutics, 2020 Figure 1. Development of neutralizing antibodies for treating COVID-19. In the receptor binding stage, the S1 subunit of SARS-CoV-2 binds human ACE2 on the host cell surface. Antibodies that bind the RBD domain on the S1 subunit might block the interaction of the RBD and the ACE2. Cross- reactive antibodies (e.g., 47D11, S309, and VHH-72) that bind highly conserved epitopes on the RBDs of SARS-CoV and SARS-CoV-2 could have broad neutralization activities against viral infection. In the viral fusion stage, after the cleavage of S1 subunit, the viral fusion peptide (FP) on the S2 subunit inserts into the host cell membrane, inducing the conformational change of the S2 subunit, which forms a six-helix bundle (6-HB) with the HR1 and HR2 trimers. Antibodies (e.g., 1A9 against SARS-CoV) that target the HR domains might block viral fusion. Ab, antibody. the bat coronavirus RaTG13, indicating that the bat coro- Antibody sources may include memory or plasma B navirus might be the origin of the SARS-CoV-2 [10]. Fur- cells from recovered patients, phage, yeast and ribosome thermore, SARS-CoV-2 might be the result of a recombi- libraries, or from mouse, rabbit, monkey, and llama nation between bat (RaTG13) and pangolin coronaviruses, immunizations. Most antibodies are tested for their ability as particularly indicated in the S protein sequence [10]. to block S protein (or RBD) binding to ACE2 and The receptor binding domain (RBD) of the SARS-CoV- preventing spike-mediated membrane fusion. Antibody 2 S protein contains several novel residues that might be activity is tested either by using a pseudovirus-based introduced through recombination with the pangolin coro- neutralization assay or by a live virus-based neutralization navirus, indicating a possible critical step in the evolution assay. Animal models such as human ACE2 transgenic mice of the ability of SARS-CoV-2 to infect humans [10]. The are also summarized in their review article. structures of SARS-CoV-2 S protein trimer [11] and human In the research paper from Chengdu Medical College and ACE2 [12] have been rapidly solved using modern cryo- ABLINK Biotech Co., Ltd in China, Zeng et al. isolated electron microscopy (Cryo-EM). The affinity of the SARS- a human monoclonal antibody (named “rRBD-15”) that CoV-2 RBD for human ACE2 appears stronger than the inhibits the interaction of the RBD of SARS-CoV-2 and SARS-CoV RBD. The structural analysis of the RBD- the ACE2 and neutralizes the pseudovirus infection [5]. ACE2 complex reveals some of the key mutations on the The group used a competitive screening strategy to isolate RBD, such as F486 and N501, that form stronger contacts human antibodies from a phage display library. In the with human ACE2 [12]. Interestingly, these residues can be first round of phage panning, they followed the standard found in the pangolin coronavirus [10]. procedure by screening phage on immobilized RBD. After the first-round enrichment of RBD binders, in the 2nd and 3rd rounds, they immobilized ACE2 and added the SEARCH FOR NEUTRALIZING ANTIBODIES mixture of free RBD and a phage pool enriched from TARGETING THE RBD the 1st round. Phage that bind RBD at epitopes different In the review paper from Dr Zhiqiang An’s group in the from the ACE2-binding site were captured by the immo- University of Texas Health Science Center at Houston, Ku bilized ACE2 to form a “sandwich” complex. Phage that et al. summarized current findings on the structures and competed with ACE2 for RBD were in the supernatant functions of SARS-CoV-2 viral proteins. They describe along with presumably unknown amounts of nonbinders potential strategies for repurposing drugs for the treatment or nonspecific binders. The phage that bind the ACE2 site of COVID-19 and the current development of vaccines, on the RBD were then isolated by magnetic beads using plasma therapies, and neutralizing antibodies [4]. Their the histidine tag on the RBD. The key for success using review highlights the potential viral targets, screening meth- this strategy is the ratio of immobilized ACE2, free RBD, ods, in vitro and in vivo models, as well as discussing poten- and phage concentrations in solution. Therefore, they used tial antibody-dependent enhancement (ADE) and Fc engi- a low concentration of RBD (1 μg/ml) close to the EC neering for developing neutralizing antibodies for treating value of RBD binding to ACE2 and a low concentration COVID-19 patients. In particular, their review describes 1 × 10 pfu of the phage they enriched from 1st round of major screening strategies for the discovery and develop- panning on RBD. Standard phage panning protocols used ment of SARS-CoV-2 neutralizing antibodies and provides about 100 times more phage or about 1 × 10 pfu. In this several representative examples using these methods. way, they expected to reduce nonspecific binding of phage. Antibody Therapeutics, 2020 111 ISOLATION OF CROSS-NEUTRALIZING the cross-neutralizing activity against SARS-CoV-2. The ANTIBODIES structure complex of 47D11 and the RBD (or the S1/S protein) would reveal a novel conserved site on the RBD Several important questions are raised in the development for broad-neutralizing antibodies against SARSr-CoVs. of neutralizing antibodies for treating COVID-19. Could In addition to 47D11, another human antibody (S309) such antibodies be cross-reactive with other SARS-related isolated from memory B cells of a SARS survivor infected CoVs (SARSr-CoVs)? Could such cross-reactive antibodies in 2003 neutralizes SARS-CoV-2 [18]. Interestingly, S309 have neutralizing activities for all SARSr-CoVs? What recognizes a glycan-containing epitope on the RBD in both would be ideal targets or epitopes for cross-neutralizing the open and closed S states. The cryo-EM structure of antibodies? Selection of cross-neutralizing antibodies the complex of S309 and SARS-CoV-2 S protein indicates would be useful for treating not only current COVID-19 that the antibody engages an epitope distinct from the patients but also future SARSr-CoV infections. ACE2 binding motif and would not clash with ACE2 for The RBD of the S protein is the primary target its binding to S protein. The glycan recognition of S309 for neutralizing antibodies. Many known neutralizing implies the importance of the N-glycans in SARS-CoV-2 S protein. Furthermore, antibody cocktails containing S309 antibodies, including S230, m396, and 80R, are specific further improved SARS-CoV-2 neutralization and might for SARS-CoV RBD but fail to bind SARS-CoV-2 even at be useful for preventing or mitigating virus escape mutants. the concentration up to 1 μM [11]. Polyclonal antibodies This supports the idea that antibody cocktails could be from mice immunized with a stabilized SARS-CoV S more effective than single antibody therapy. Besides human protein can inhibit SARS-CoV-2 entry into target cells. neutralizing antibodies, a single domain camelid antibody This suggests that immunity against one SARSr-CoV can (VHH-72), commonly called “nanobody”, was isolated potentially provide protection against related SARS-CoV from a llama immunized with SARS-CoV S and MERS- [13]. In contrast, another study showed that polyclonal CoV S. This nanobody showed reactivity with SARS-CoV- rabbit anti-SARS-CoV S1 antibodies (T62) inhibited entry 2 S protein by binding to a highly conserved epitope on of SARS-CoV, but not SARS-CoV-2 pseudovirus [14]. the RBD partially overlapping the CR3022 binding site In addition, sera from recovered SARS and COVID-19 [19]. However, unlike CR3022, the bivalent VHH-72-Fc patients show only modest cross-neutralization, suggesting that recovery from one SARSr-CoV infection might not fusion protein not only prevents the binding of ACE2 protect against the other. A recent report showed that but also has neutralizing activity against SARS-CoV-2 none of the monoclonal antibodies isolated from SARS- pseudovirus. The neutralizing effects of 47D11 and VHH- CoV-2 infected individuals by single B-cell sorting were 72 suggest that co-immunizing animals with S proteins cross-reactive with the RBD of SARS-CoV [15]. In a from SARS-CoV-2 and other coronavirus may produce research article published in our journal, Zeng et al. did not potent broad-neutralizing antibodies against SARS-CoV- test the cross-reactivity of the rRBD-15 human antibody 2 by targeting the RBD. Single domain antibodies have for SARS-CoV RBD [5]. In the review article, Ku et al. unique binding features [20, 21], so they can bind novel viral discusses two unique cross-reactive antibodies, CR3022 conformational epitopes including highly conformational and 47D11, which bind highly conserved epitopes in the and/or buried sites unreachable by conventional antibodies. RBD [4]. CR3022 is an antibody that binds both SARS- Besides their unique binding features, other advantages CoV and SARS-CoV-2 RBDs, but it cannot neutralize include the construction of multivalent/multispecific molecules and thermostability/chemostability [22]. For SARS-CoV-2 as it does SARS-CoV [16]. More recently, respiratory infection, single domain antibodies might be Wang et al. identified the 47D11 monoclonal antibody particularly attractive because they might be administered that can neutralize both SARS-CoV and SARS-CoV- as an inhaler directly to the site of infection [19]. Both 2 infection [17]. The 47D11 antibody was isolated from 47D11 and S309 are fully human IgG molecules, whereas transgenic mice immunized sequentially with purified S VHH-72 is a single domain antibody derived from a llama proteins of different coronaviruses (HCoV-OC43, SARS- heavy chain antibody that has not been humanized yet. For CoV, and MERS-CoV). The transgenic mice produce therapeutic applications, the camelid-specific sequences in chimeric immunoglobulins with human variable regions the framework may need to be mutated to their human and rodent constant regions. Four of 51 antibodies specific heavy chain variable domain equivalent [23]. Its suitability for the S protein of SARS-CoV show cross-reactivity for prophylactic and therapeutic treatments remains to be with the S1 subunit of SARS-CoV-2. Among them, the determined. 47D11 antibody exhibits the cross-neutralizing activity of SARS-CoV-2 and SARS-CoV in cell culture. Interestingly, It might be useful to analyze the mutations of SARS- 47D11 binds the RBD but does not block the interaction CoV-2 as it spreads worldwide, so neutralizing antibodies of RBD and ACE2, indicating that 47D11 might bind a can be effective for multiple strains of the virus [24–26]. Up highly conserved epitope of the RBD distinct from the to now, most of the mutations found in the RBD of SARS- ACE2 binding site. Previous studies indicate that SARS- CoV-2 are of low frequency [26]. The G476S mutation was CoV RBD antibodies that block the interaction of the located in the binding interface of the RBD with the ACE2, RBD and ACE2 are not cross-reactive with SARS-CoV- although it occurred in early samples and diminished in 2RBD [11]. CR3022 also binds a highly conserved epitope late samples, indicating that the virus with mutations in on the RBD and binds both SARS-CoV and SARS- the critical functional site might not have advantage for its CoV-2 RBDs [16], but unlike 47D11, it does not have survival or spread. 112 Antibody Therapeutics, 2020 NEUTRALIZING ANTIBODIES TARGETING suggesting that in addition to ACE2, HSPGs might be NON-RBD REGIONS essential for SARS-CoV entry into host cells. Blocking the HSPGs on human cells by therapeutic antibodies is While the RBD is the focus for the development of neu- worth investigating as another potential strategy for treat- tralizing antibodies against SARS-CoV-2, the function of ing COVID-19. non-RBD regions is poorly understood. Recently, an anti- body (4A8) isolated from convalescent COVID-19 patients shows the binding on the N-terminal domain (NTD) of the SARS-CoV-2 S protein and exhibits high neutralization PERSPECTIVE potency SARS-CoV-2. The structural analysis has con- Many antibodies capable of neutralizing specifically either firmed its binding to the NTD, not the RBD which directly SARS-CoV or SARS-CoV-2, but not both, have been iden- interacts with ACE2, demonstrating a new vulnerable epi- tified and reported through many methodologies. A very tope in the S1 subunit as a target of neutralizing antibodies few and very special SARS-CoV and SARS-CoV-2 cross- for treating COVID-19 [27]. neutralizing antibodies have also been documented, includ- Antibodies that target the S protein beyond the S1 ing 47D11, S309, and VHH-72, among which the former subunit have rarely been reported. The S2 subunit, in two, which are human monoclonal antibodies, are ACE2 particular heptad repeat (HR) loops including HR1 and nonblockers, whereas the third one, which is a llama single HR2 domains, required for membrane fusion might be domain antibody, is an ACE2 blocker. another target. The 1A9 antibody is the only known Competitive phage display panning might be a new way monoclonal antibody that binds the HR2 domain on to identify both ACE2 blockers and nonblockers. Even S2 subunit of SARS-CoV [28](Fig. 1). A more recent though Zeng et al. only reported the identification of one study showed that SARS-CoV-2 had a superior plasma antibody, rRBD-15, that blocked ACE2 and neutralized membrane fusion capacity compared with that of SARS- SARS-CoV-2 [5], the same phage display competitive pan- CoV [29]. The X-ray crystal structure of six-helical bundle ning strategy could also be used to identify antibodies (6-HB) core of the HR1 and HR2 domains in the SARS- that do not block the interaction between S protein and CoV-2 S protein S2 subunit has also been solved [29]. A ACE2 yet still neutralize viral infections. More importantly, lipopeptide (EK1C4) that disturbs viral 6-HB formation by with S proteins of both SARS-CoV and SARS-CoV-2 as binding the HR1 domain can inhibit the fusion of SARS- competitors, this competitive panning strategy could be CoV-2 as well as other human coronavirus including SARS- utilized to identify both ACE2 blocking and nonblocking CoV and MERS-CoV, suggesting that a broad inhibitor antibodies against both viruses with functional profiles targeting the HR region should be tested for the treatment similar to 47D11, S309, and VHH-72, respectively. of infection by current and future SARSr-CoVs. In the last 20 years, human coronaviruses have infected Besides widely studied protein targets, glycan targets humans and causes three major outbreaks due to SARS- might be worth exploring as well. The S protein of SARS- CoV, MERS-CoV, and SARS-CoV-2. An urgent and CoV-2 is highly glycosylated [11]. Isolation of the S309 important challenge in modern medicine is whether we neutralizing antibody that recognizes a glycan-containing could identify a so-called “universal” target or strategy epitope on the RBD indicates that glycosylation on the for inhibiting SARSr-CoV or even all coronaviruses. The S protein would affect the development of neutralizing molecular mechanisms of SARS-CoV-2 infection are not antibodies targeting SARS-CoV-2 [18]. yet fully understood. More research on the SARS-CoV-2 biology is urgently needed. Current challenges in develop- ing neutralizing antibodies against SARS-CoV-2 include HOST CELL TARGETS mutations in less conserved region of S1 subunit, possibly On the host cell, the primary target is the viral entry protein, antigen drift, immunodominant epitope, ADE potentially ACE2. It has been proposed that recombinant ACE2 might induced by nonneutralizing antibodies, or increased be used as a potential inhibitor to block the virus entry affinity of viral S protein for ACE2 [26]. It is important [30]. The ACE2-human IgG1 Fc fusion has been engi- to identify and develop neutralizing antibodies, such as neered. The fusion protein can neutralize pseudoviruses 47D11, S309, and VHH-72, against highly conserved that express the S proteins of SARS-CoV-2 or SARS-CoV region of RBD or S1, to combat not only various strains in cell culture [31]. of SARS-CoV-2 but also broadly against other SARSr- Heparan sulfate proteoglycans (HSPGs) provide the ini- CoVs. Furthermore, a single monoclonal antibody therapy tial sites for the virus to make primary contact with the might not be enough. There might be different strains of the cell surface [32]. My laboratory research has been focused virus that cannot be recognized by the antibody. Mutations on the biology of HSPGs, in particular glypicans, and in the virus can lead to escape variants [38]. Multiple their roles as targets in cancer therapy [33]. Using one of strategies and combination of multiple mechanisms are our human antibodies (HS20) specific for heparan sulfate highly expected as described in MERS [39] and SARS oligosaccharides with high affinity [34–36], we and col- [38] antibody development. A combination of two (or laborators previously showed that the HS20 antibody can more) antibodies that recognize different parts including block the attachment of pathogenic polyomaviruses on cells both neutralizing and nonneutralizing epitopes (e.g., RBD, [37]. Interestingly, treatment of the cells with heparinase or NTD, HR, and glycan) of the viral surface that interact with exogenous heparin prevents the binding of the S protein human cells might be the most effective. 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Journal
Antibody Therapeutics – Oxford University Press
Published: May 20, 2020
Keywords: SARS-CoV-2; SARS-CoV; COVID-19; neutralizing antibody; spike (S) protein