Genetic and structural basis for SARS-CoV-2 variant neutralization by a two-antibody cocktail

Dong, Jinhui; Zost, Seth J.; Greaney, Allison J; Starr, Tyler N; Dingens, Adam S.; Chen, Elaine C.; Chen, Rita E.; Case, James Brett; Sutton, Rachel E.; Gilchuk, Pavlo; Rodríguez, Jessica; Armstrong, Erica; Gainza, Christopher; Nargi, Rachel S.; Binshtein, Elad; Xie, Xuping; Zhang, Xianwen; Shi, Pei–Yong; Logue, James; Weston, Stuart; McGrath, Marisa E.; Frieman, Matthew B.; Brady, Tyler; Tuffy, Kevin M.; Bright, Helen; Loo, Yueh–Ming; McTamney, Patrick M.; Esser, Mark T.; Carnahan, Robert H.; Diamond, Michael S.; Bloom, Jesse D.; Crowe, James E.

doi:10.1038/s41564-021-00972-2

Cited by 278 publications

(247 citation statements)

References 82 publications

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“…Consistent with previous studies, the majority of isolated SARS-CoV-2 mAbs were similar to germline sequences, in agreement with the observation that germline-encoded residues play an important role in the binding of several potent neutralizing antibodies across multiple classes 4 , 49 . Altogether, these data demonstrate that NTD-RBD mAb combinations offer low-dose protection in vivo, likely leveraging complementary Fab-mediated and Fc-mediated antiviral activities.…”

Section: Discussionsupporting

confidence: 91%

“…Comparing the antibody gene usage and targeted epitope to previously published antibodies (Supplementary Table 1 ), WRAIR-2125 shares heavy-chain (IGHV3-30*18) and light-chain (IGKV1–39*01) genes with recurring antibodies observed in multiple donors 14 , but with alternate D (IGHD3–22) and J (IGHJ1) gene combinations specific to WRAIR-2125. The WRAIR-2125 epitope shares a resemblance to a class of F486-targeting IGHV1–58/IGKV3–20-derived mAbs such as S2E12 that belong to a public clonotype 4 , 16 , 40 , despite little sequence identity (Supplementary Table 1 ). In addition, WRAIR-2125 approaches the RBD from a different angle, and uses predominantly CDR H loops to recognize F486 (Extended Data Fig.…”

Section: Resultsmentioning

confidence: 99%

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Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations

et al. 2021

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Prevention of viral escape and increased coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern require therapeutic monoclonal antibodies (mAbs) targeting multiple sites of vulnerability on the coronavirus spike glycoprotein. Here we identify several potent neutralizing antibodies directed against either the N-terminal domain (NTD) or the receptor-binding domain (RBD) of the spike protein. Administered in combinations, these mAbs provided low-dose protection against SARS-CoV-2 infection in the K18-human angiotensin-converting enzyme 2 mouse model, using both neutralization and Fc effector antibody functions. The RBD mAb WRAIR-2125, which targets residue F486 through a unique heavy-chain and light-chain pairing, demonstrated potent neutralizing activity against all major SARS-CoV-2 variants of concern. In combination with NTD and other RBD mAbs, WRAIR-2125 also prevented viral escape. These data demonstrate that NTD/RBD mAb combinations confer potent protection, likely leveraging complementary mechanisms of viral inactivation and clearance.

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations

et al. 2021

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“…AZD7442 is the combination of two human mAbs initially isolated from convalescent patients after SARS-CoV-2 infection and later engineered to be long-acting IgG molecules. The mAbs, COV2-2130 (AZD1061/cilgavimab) and COV2-2196 (AZD8895/tixagevimab), recognize and simultaneously bind to two distinct non-overlapping epitopes on the virus RBD in the “up” configuration [ 100 , 101 ]. COV2-2130 and COV2-2196 both have neutralizing abilities, with IC 50 values of 1.6 ng/mL and 0.7 ng/mL in pseudovirus assays, and IC 50 values of 107 ng/mL and 15 ng/mL in FRNT, respectively (Table 1 ).…”

Section: Therapeutic Absmentioning

confidence: 99%

Monoclonal antibodies for COVID-19 therapy and SARS-CoV-2 detection

et al. 2022

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The coronavirus disease 2019 (COVID-19) pandemic is an exceptional public health crisis that demands the timely creation of new therapeutics and viral detection. Owing to their high specificity and reliability, monoclonal antibodies (mAbs) have emerged as powerful tools to treat and detect numerous diseases. Hence, many researchers have begun to urgently develop Ab-based kits for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ab drugs for use as COVID-19 therapeutic agents. The detailed structure of the SARS-CoV-2 spike protein is known, and since this protein is key for viral infection, its receptor-binding domain (RBD) has become a major target for therapeutic Ab development. Because SARS-CoV-2 is an RNA virus with a high mutation rate, especially under the selective pressure of aggressively deployed prophylactic vaccines and neutralizing Abs, the use of Ab cocktails is expected to be an important strategy for effective COVID-19 treatment. Moreover, SARS-CoV-2 infection may stimulate an overactive immune response, resulting in a cytokine storm that drives severe disease progression. Abs to combat cytokine storms have also been under intense development as treatments for COVID-19. In addition to their use as drugs, Abs are currently being utilized in SARS-CoV-2 detection tests, including antigen and immunoglobulin tests. Such Ab-based detection tests are crucial surveillance tools that can be used to prevent the spread of COVID-19. Herein, we highlight some key points regarding mAb-based detection tests and treatments for the COVID-19 pandemic.

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“…These NAbs such as AZD8895 36 , REGN-10933 42 , and BD-836 45 bind to the left shoulder of RBD, often focusing on the far tip (Fig. 2h).…”

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confidence: 99%

Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies

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Jian

et al. 2021

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The SARS-CoV-2 B.1.1.529 variant (Omicron) contains 15 mutations on the receptor-binding domain (RBD). How Omicron would evade RBD neutralizing antibodies (NAbs) and humoral immunity requires immediate investigation. Here, we used high-throughput yeast display screening to determine the RBD escaping mutation profiles for 247 human anti-RBD NAbs identified from SARS-CoV/SARS-CoV-2 convalescents and vaccinees. Based on the results, NAbs could be unsupervised clustered into six epitope groups (A-F), which is highly concordant with knowledge-based structural classifications. Strikingly, various single mutations of Omicron could impair NAbs of different epitope groups. Specifically, NAbs in Group A-D, whose epitope overlaps with ACE2-binding motif, are largely escaped by K417N, N440K, G446S, E484A, Q493K, and G496S. Group E (S309 site) and F (CR3022 site) NAbs, which often exhibit broad sarbecovirus neutralizing activity, are less affected by Omicron, but still, a subset of NAbs are escaped by G339D, S371L, and S375F. Furthermore, B.1.1.529 pseudovirus neutralization and RBD binding assay showed that single mutation tolerating NAbs could also be escaped due to multiple synergetic mutations on their epitopes. In total, over 85% of the tested NAbs are escaped by Omicron. Regarding NAb drugs, LY-CoV016/LY-CoV555 cocktail, REGN-CoV2 cocktail, AZD1061/AZD8895 cocktail, and BRII-196 were escaped by Omicron, while VIR7831 and DXP-604 still function at reduced efficacy. Together, data suggest Omicron could cause significant humoral immune evasion, while NAbs targeting the sarbecovirus conserved region remain most effective. Our results offer instructions for developing NAb drugs and vaccines against Omicron and future variants.

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Genetic and structural basis for SARS-CoV-2 variant neutralization by a two-antibody cocktail

Cited by 278 publications

References 82 publications

Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations

Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations

Monoclonal antibodies for COVID-19 therapy and SARS-CoV-2 detection

Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies

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