key: cord-0682710-k2rk9vjo
authors: Xiang, Rong; Wang, Yang; Wang, Lili; Deng, Xiaoqian; Huo, Shanshan; Jiang, Shibo; Yu, Fei
title: Neutralizing monoclonal antibodies against highly pathogenic coronaviruses
date: 2021-12-30
journal: Curr Opin Virol
DOI: 10.1016/j.coviro.2021.12.015
sha: d3ec0f02c9523de7a65b28878dc628da18276f14
doc_id: 682710
cord_uid: k2rk9vjo

The pandemic of Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome 2 coronavirus (SARS-CoV-2) is a continuing worldwide threat to human health and social economy. Historically, SARS-CoV-2 follows SARS and MERS as the third coronavirus spreading across borders and continents, but far more dangerous with long-lasting symptomatic consequences. The current situation is strong evidence that coronaviruses will continue to be pathogens of consequence in the future, thus calling for the development of neutralizing antibody-based prophylactics and therapeutics for prevention and treatment of COVID-19 and other human coronavirus diseases. This review summarized the progresses of developing neutralizing monoclonal antibodies against infection of SARS-CoV-2, SARS-CoV, and MERS-CoV, and discussed their potential applications in prevention and treatment of COVID-19 and other human coronavirus diseases.

Similar to the use of hybridoma technology, researchers used EBV to infect antibody-secreting B cells in order to construct immortal cell lines that stably express antibodies. In this way, a pool of human NMAbs was screened out, such as S3.1 and S230.15 [16, 19] (Table 1) .

Fully humanized NMAbs have been developed from the human immunoglobulin G (IgG) transgenic mouse, XenoMouse®, immunized with the SARS-CoV S protein [20] . The NMAbs 68 and 201 targeting the NTD and RBD, respectively, identified from the immunized transgenic mice. Mice receiving 40 mg/kg of either NMAb prior to SARS-CoV challenge were completely protected [21] ( Table 1) .

Owing to limited human trials, the development of animal immunization and hybridoma technology has substantially enriched SARS-CoV antibody research. A large number of animal-derived NMAbs were screened out, such as F26G18, and the corresponding chimeric antibodies were obtained by antibody humanization. These chimeric NMAbs were shown to target RBD and exert antiviral effects by inhibiting ACE2 binding to RBD [22] [23] [24] . Similarly, many NMAbs with strong neutralizing activity against SARS-CoV were identified, including 1A5, 2C5, and 341C, all targeting RBD [25, 26] . To explore effective targets, researchers immunized mice with different regions of the S protein as antigens and obtained S34 and S84 with correspondingly different targets [27] . The mutation rate of the S2 region was much slower, compared to S1, resulting in the development of more broad-spectrum S2-targeting antibodies against SARS-CoV mutant strains [28, 29] . Accordingly, researchers immunized mice with S2 as the antigen and screened a number of NMAbs targeting S2, among which 1A9 was the most potent [30] [31] [32] .

J o u r n a l P r e -p r o o f NMAbs m336, m337, and m338 that were identified from a phage-displayed Fab library from healthy donors showed potent antiviral activity against MERS-CoV pseudovirus [33, 34] . The 3B11 was screened from a nonimmune phage-displayed single chain fragment variable (scFv) library [35] .

In addition, MERS-4 and MERS-27 were identified from a yeast-displayed scFv library from healthy donors [36] . These antibodies all targeted the RBD and inhibited viral invasion by blocking the binding between RBD and DPP4 (Figure 2b ). Originating from MERS-CoV-infected patients, MCA1 is an RBD-targeting NMAb screened from a phage display library [37] .

In addition to constructing phage libraries, immortalized B cell-based EBV infection has also been performed in antibody studies. For MERS-CoV, LCA60 was screened in this way [38] .

REGN3051 and REGN3048 are fully humanized NMAbs screened from transgenic mice [39] (Table   1) . A group of chimeric antibodies were also screened from transgenic mice [40] . Among them, 7.7g6, 1.6f9, 1.2g5 and 4.6e10 target RBD, while 1.6c7 and 3.5g6 target S2 to prevent viral invasion by inhibiting the conformational change of S2 [40] (Table 1) .

Many NMAbs, such as CDC2-C2 [41] and MERS-GD27 [42, 43] , have also been obtained using a fast and efficient method known as cloning and expressing antibody genes [44] .

A large number of mouse-derived antibodies have been screened. Among of them, Mersmab1 [45] , 4C2 and 2E6 were screened for targeting RBD and subsequently produced humanized antibodies that showed potent antiviral activity in vitro and in vivo [46, 47] . RBD-23D3, RBD-25E4, and RBD-40G7, all targeting RBD, were identified with high cross-neutralizing activity among mutant isolates [48] .

NMAbs D12 and F11 targeting RBD, G2 targeting NTD, and G4 targeting S2 subunit were all identified by immunized mice [49, 50] . Screened by hybridoma technology, 5F9 and 7D10 are murine NMAbs targeting the NTD [51, 52] (Table 1 ). In addition to murine-derived antibodies, researchers J o u r n a l P r e -p r o o f have obtained neutralizing antibodies from immunized animals of other species. For example, JC57-14, targeting RBD, was screened from macaques, and JC57-14 and FIB-H1, targeting non-RBD regions of S1, were also screened from macaques [41] . Furthermore, JC57-14 could protect DPP4-transgenic mice against MERS-CoV infection [41] .

In addition to conventional antibodies, heavy-chain-only antibodies (HCAbs) produced by camelids contain a single-variable domain (VHH), instead of two variable domains (VH and VL), of conventional IgG antibodies that affords the equivalent effect [53] . VHH shows affinities and specificities for antigens comparable to conventional antibodies. VHHs can be easily constructed into multivalent formats and show higher thermo-stability and chemo-stability, compared to most other antibodies [54] [55] [56] [57] [58] [59] . VHHs are also less susceptible to steric hindrance during binding [60] . For MERS-CoV, VHH-83, NbMS10 and VHH-55 were screened from antibody libraries of immunized camels [61] [62] [63] (Table 1) .

Ab1, rRBD-15 and 5A6 were screened from nonimmune antibody libraries of healthy humans and showed strong neutralizing activity against SARS-CoV-2 in vitro or in vivo [64] [65] [66] . In addition, to solve the immunogenicity problem of heterologous single-domain antibodies, researchers constructed a fully human single-domain antibody phage-displayed library by modifying healthy human heavy chains to obtain soluble and highly stable single-domain antibodies [67] , and a pool of NMAbs against SARS-CoV-2 was identified. Among of them, n3130 had the most potency in targeting SARS-CoV-2 S1 [67] . However, it did not effectively inhibit the binding of RBD to its receptor ACE2.

CT-P59, screened from a patient antibody library [68] , showed good therapeutic efficacy against SARS-CoV-2 infection in vitro and in vivo and was used in clinical trials. Similarly, 910-30 and 2B11 were identified from convalescent patient-derived yeast and phage display libraries, J o u r n a l P r e -p r o o f respectively [69, 70] . Notably, a number of cross-reactive NMAbs (like ADI-55689) against SARS-CoV and SARS-CoV-2 were identified from yeast-displayed libraries established with B cells of SARS convalescent patients based on the genome similarity between SARS-CoV and SARS-CoV-2 [71] . Through genetic mutations, diversity was introduced into the heavy and light chain variable genes of ADI-55688, ADI55689 and ADI-56046, and three highly active antibodies were identified, among which, ADG-2 showed broad-spectrum neutralizing activity against clade 1 sarbecoviruses [72] . 

Antibody gene cloning and sequencing technologies for identification of SARS-CoV-2 NMAbs from B cells sorted from COVID-19 patients are being used more frequently, and several high-throughput screening methods have been established [74, 75] , considerably reducing the time required for antibody development and enriching antibody diversity. These NMAbs showed strong neutralizing activity in vitro or in vivo. Most of them target the RBD in S1 subunit, and their mechanism of action is summarized in Table 1 . Also, NMAbs targeting SARS-CoV-2 NTD, e.g.,4A8 and 4-8, were isolated in this way [76] [77] [78] . A large group of RBD-targeting NMAbs, including BD-368-2, P2C-1F11, CB6, S2H13 and C1A-B12, could interfere with the binding of RBD to the receptor ACE2, showing strong neutralizing activity in vitro [74, [79] [80] [81] [82] . CB6 showed potent in vivo efficacy, protecting rhesus macaques against SARS-CoV-2 infection in both prophylactic and treatment settings [79] . CC12.1 exhibited the most potent in vitro neutralizing activity and completely protected Syrian hamsters against the challenge of a Washington strain (USA-WA1/2020) in vivo [75] . CV07-209 could reduce lung pathology in a COVID-19 hamster model [83] . LY-CoV555 protected against SARS-CoV-2 infection in nonhuman primates and showed potent neutralization effect and good safety profiles in clinical trials [84, 85] (Table 1) . Notably, B38 and H4 target different neutralizing epitopes in RBD [86] . No competition takes place between the two NMAbs; J o u r n a l P r e -p r o o f therefore, the combination results in an ideal cocktail candidate for COVID-19 therapy, which is also effective in preventing escape mutations. Such antibody pairs are not uncommon in SARS-CoV-2 antibody studies, and their combination has shown better neutralizing activity compared to the use of each compound alone. Examples are COV2-2196/COV2-2130 [87, 88] , S2M11/S2E12 [89] and REGN10933/REGN10987 (REGN-CoV2) [90] [91] [92] (Figure 2c ). Further, REGN-CoV2 has shown neutralization effect and safety in clinical trials [93] (Table 1) . Similarly, researchers screened a large set of NMAbs with different targets against SARS-CoV-2 [94] . Among them, COVA1-18 and COVA2-15 showed the strongest antiviral activity [94] . Many NMAbs, such as MW05 [95] , 311mab-31B5/311mab-32D4 [96] , C121 [97] and CV30 [98, 99] were identified from the sorted SARS-CoV-2 RBD-specific, IgG class-switched memory B cell of COVID-19 convalescent patients using antibody gene cloning technology. They have shown neutralizing activity against SARS-CoV-2 in vitro and in vivo through competition with ACE2 in binding with RBD (Table 1 ). It was found that epitopes of some NMAbs are relatively conservative in sequence (e.g., DH1047, A19-46.1, S2X259 and CV1-30), and these NMAbs show cross-neutralizing activity against SARS-CoV-2 variants and other sarbecoviruses [100] [101] [102] [103] [104] [105] . Like these NMAbs, EY6A targets a conserved footprint in RBD that is distinct from receptor binding motifs, and it inhibits viral invasion by altering the pre-fusion conformation of S proteins [106] . Moreover, it showed cross-reactivity against SARS-CoV S1 protein [106] .

2H2 and 3C1 were identified by using animal immunization and hybridoma technology. Because these two NMAbs target different epitopes in SARS-CoV-2 RBD, they can be used in combination, i.e., a cocktail therapy (Figure 2c ). Their combination exhibited more potent neutralizing activity against authentic SARS-CoV-2 infection in vitro [107] . Similarly, 7D6 and 6D6 were identified from mice immunized with SARS-CoV-2 S protein, and SARS-CoV-2/SARS-CoV S protein/MERS-CoV RBD, respectively, showing cross-neutralizing activity against SARS-CoV and SARS-CoV-2 as well as its variants [108] . 7B11 and 18F3, SARS-CoV neutralizing mAbs by targeting different neutralizing epitopes in RBD of SARS-CoV S protein, were identified from mice immunized with SARS-CoV S-RBD [109] .

J o u r n a l P r e -p r o o f

H014, a humanized SARS-CoV-2 NMAb, was originally identified from a phage display antibody library generated from RNAs of the peripheral lymphocytes of SARS-CoV RBD-immunized mice. It exhibited potent neutralizing activity against SARS-CoV-2 infection in vitro by blocking RBD-ACE2 binding through steric hindrance [110] .

47D11, a chimeric antibody with human variable region and rat constant region, was identified from transgenic mice, showing cross-neutralizing reactivity against SARS-CoV and SARS-CoV-2 [111] .

3F11 was identified from a phage display library from nonimmune camel and was expressed by fusion with human IgG Fc fragment in order to overcome the limitations of sdAbs [58, 112] . H11 was also identified from a naive llama phage display antibody library. Researchers obtained H11-H4 and H11-D4 with more affinity for SARS-CoV-2 RBD by random mutation of H11, both exhibiting strong antiviral activity in vitro [113] .

More commonly, camels are immunized to obtain sdAbs. VHH-72, was identified from a phage display library generated cells of a llama immunized with SARS-CoV and MERS-CoV S proteins multiple times showed cross-neutralizing activity against pseudotyped SARS-CoV, MERS-CoV and SARS-CoV-2 [63] . NIH-CoVnb-112 was isolated from an immune llama phage display library [114] .

W25 was identified from a VHH E. coli-displayed antibody library of immune alpaca. It showed potent neutralizing activity against the D614G isolate, whether monomer or dimer [115] . Another sdAb that exhibited strong neutralizing activity in multimeric form is VHH E (Figure 2c) , which was screened from an immune camel phage display library [116] . The trimeric VHH EEE inhibits infection against both SARS-CoV-2 pseudovirus and authentic virus. The combination of VHH E and VHH V, targeting different sites of the RBD, is effective in preventing escape mutations, whereas multimers could not [116] . In a similar method, Ty1 was screened from an alpaca phage display library [117] . In addition, a large number of nanobodies have been screened as candidate drugs for the treatment of COVID-19 [118] [119] [120] .

J o u r n a l P r e -p r o o f

Coronaviruses constitute a large group in nature, and genome sequence analysis shows that many coronaviruses are highly homologous to SARS-CoV, MERS-CoV or SARS-CoV-2 [121] . Therefore, coronaviruses may continue to threaten human health. Rapid development of therapeutic and prophylactic drugs is essential, both for coronaviruses that have already emerged to infect humans and for those that may emerge in the future. With the development of high-throughput screening technology for antibodies, the cycle time for antibody development is shortening. Antibody drugs could be the antiviral drug of choice based on their advantages of high targeting and low side effects.

Moreover, different species of coronaviruses have conserved loci between their genomes, and it may be possible to design and screen antibodies with broad-spectrum antiviral activity based on these loci.

Many studies on the mechanism of NMAbs with cross-neutralizing activity against SARS-CoV-2 variants and other sarbecoviruses have shown that the targets of these NMAbs are relatively conservative [85, [100] [101] [102] [103] 105] . In a recent study, 41 RBD-directed NMAbs were classified into seven antibody communities with distinct footprints and competition profiles [122] . A number of NMAb cocktails consist of NNAbs from different RBD-directed antibody communities showed enhanced neutralizing potency. However, the potency of some NNAbs in the combinations is compromised by emerging SARS-CoV-2 variants. Improving the neutralizing activity of these NMAbs through other means (e.g., mutation and multimeric forms) greatly enhance their application prospects [72, 122] . Therefore, in addition to the combination strategy, the in vitro modification of antibodies is also crucial to improve the neutralizing activity of the antibody drugs. Of course, the acceleration of antibody drug formation, the miniaturization of effective antibody molecules and the improvement of in vivo longevity are expected.

No conflicts of interest are declared.

This work was supported by grants from the National Natural Science Foundation of China J o u r n a l P r e -p r o o f

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