Characterization of neutralizing antibody with prophylactic and therapeutic efficacy against SARS-CoV-2 in rhesus monkeys

Wang, Shuang; Peng, Yun; Wang, Rongjuan; Jiao, Shasha; Wang, Min; Huang, Weijin; Shan, Chao; Jiang, Wen; Li, Zepeng; Gu, Chunying; Chen, Ben; Hu, Xue; Yao, Yanfeng; Min, Juan; Zhang, Huajun; Chen, Ying; Gao, Ge; Tang, Peipei; Li, Gang; Wang, An; Wang, Lan; Zhang, Jinchao; Chen, Shuo; Gui, Xun; Yuan, Zhiming; Liu, Datao

doi:10.1038/s41467-020-19568-1

Cited by 64 publications

(81 citation statements)

References 23 publications

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“…Using a viral dynamic model, we estimated that COVA1-18 reduced viral infectivity by >95% and 99.9% in nasopharyngeal and tracheal compartments, respectively. The robustness of these results are reinforced by the high challenge dose that we used, which was 10 to 100-fold higher than in other NHP studies evaluating NAbs for PrEP against SARS-CoV-2 [29][30][31][32][33][34] . In fact, the model allowed us to predict, without using additional animals, that protection could be achieved with lower doses of 5 mg kg -1 and 1 mg kg -1 with an inoculum dose of 10 5 or 10 4 PFU, both in prophylactic and therapeutic settings (Extended Data Fig.…”

mentioning

confidence: 58%

“…Thus, there is an urgent need to develop effective therapeutics, in particular for individuals with high risk of severe disease. Pre-clinical and clinical studies to evaluate SARS-CoV-2 NAbs for prophylaxis and/or treatment and such studies have supported the implementation of several NAb candidates and NAb cocktails for emergency use 22,[29][30][31][32][33][34][35] . However, the narrow efficacy range of FDA-approved NAbs [4][5][6] , together with rapidly spreading new variants complicate treatment strategies [36][37][38][39] , highlights the need for additional treatment options, including potent NAbs such as COVA1- 18.…”

Section: Discussionmentioning

confidence: 99%

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COVA1-18 neutralizing antibody protects against SARS-CoV-2 in three preclinical models

Grand

Maisonnasse

Aldon

et al. 2021

Preprint

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One year into the Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), effective treatments are still needed1–3. Monoclonal antibodies, given alone or as part of a therapeutic cocktail, have shown promising results in patients, raising the hope that they could play an important role in preventing clinical deterioration in severely ill or in exposed, high risk individuals4–6. Here, we evaluated the prophylactic and therapeutic effect of COVA1-18 in vivo, a neutralizing antibody isolated from a convalescent patient7 and highly potent against the B.1.1.7. isolate8,9. In both prophylactic and therapeutic settings, SARS-CoV-2 remained undetectable in the lungs of COVA1-18 treated hACE2 mice. Therapeutic treatment also caused a dramatic reduction in viral loads in the lungs of Syrian hamsters. When administered at 10 mg kg− 1 one day prior to a high dose SARS-CoV-2 challenge in cynomolgus macaques, COVA1-18 had a very strong antiviral activity in the upper respiratory compartments with an estimated reduction in viral infectivity of more than 95%, and prevented lymphopenia and extensive lung lesions. Modelling and experimental findings demonstrate that COVA1-18 has a strong antiviral activity in three different preclinical models and could be a valuable candidate for further clinical evaluation.

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mentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

COVA1-18 neutralizing antibody protects against SARS-CoV-2 in three preclinical models

Grand

Maisonnasse

Aldon

et al. 2021

Preprint

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“…Other modifications to minimize the risk of ADE via unwanted effector functions (e.g., proinflammatory cytokine secretion and complement activation) have also been made, such as the introduction of double leucine to alanine mutations at position 234 and 235 (“LALA mutants”) in the Fc portion of the nAb etesevimab (LY-CoV016) and MW05 [ 45 , 46 , 49 , 50 ].…”

Section: Sars-cov-2 Nab Developmentmentioning

confidence: 99%

Neutralizing Antibody Therapeutics for COVID-19

Hurt

Wheatley

2021

Viruses

104

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The emergence of SARS-CoV-2 and subsequent COVID-19 pandemic has resulted in a significant global public health burden, leading to an urgent need for effective therapeutic strategies. In this article, we review the role of SARS-CoV-2 neutralizing antibodies (nAbs) in the clinical management of COVID-19 and provide an overview of recent randomized controlled trial data evaluating nAbs in the ambulatory, hospitalized and prophylaxis settings. Two nAb cocktails (casirivimab/imdevimab and bamlanivimab/etesevimab) and one nAb monotherapy (bamlanivimab) have been granted Emergency Use Authorization by the US Food and Drug Administration for the treatment of ambulatory patients who have a high risk of progressing to severe disease, and the European Medicines Agency has similarly recommended both cocktails and bamlanivimab monotherapy for use in COVID-19 patients who do not require supplemental oxygen and who are at high risk of progressing to severe COVID-19. Efficacy of nAbs in hospitalized patients with COVID-19 has been varied, potentially highlighting the challenges of antiviral treatment in patients who have already progressed to severe disease. However, early data suggest a promising prophylactic role for nAbs in providing effective COVID-19 protection. We also review the risk of treatment-emergent antiviral resistant “escape” mutants and strategies to minimize their occurrence, discuss the susceptibility of newly emerging SARS-COV-2 variants to nAbs, as well as explore administration challenges and ways to improve patient access.

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“…In addition, the cytokine storm has been considering to play an important role in the deterioration of COVID-19 to severe and critical illness [11,12]. The introduction of LALA mutations to the Fc region of a monoclonal antibody has been shown to halt limit the activation of macrophages, which might led to a cytokine storm and acute tissue damage [13]. These provide the fundamentals a favorable safety profile of the drug.…”

Section: Discussionmentioning

confidence: 99%

Tolerability, Safety, Pharmacokinetics, and Immunogenicity of a Novel SARS-CoV-2 Neutralizing Antibody, Etesevimab, in Chinese Healthy Adults: a Randomized, Double-Blind, Placebo-Controlled, First-in-Human Phase 1 Study

Wang

et al. 2021

Antimicrob Agents Chemother

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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to spread rapidly worldwide. This study is the first to report the tolerability, safety, pharmacokinetics (PK), and immunogenicity of a recombinant human anti-SARS-CoV-2 monoclonal antibody, etesevimab (CB6, JS016, LY3832479 or LY-CoV016), in healthy adults. This paper involves a randomized, double-blind, placebo-controlled, phase 1 study. A total of 40 participants were enrolled to receive a single intravenous dose of either etesevimab or a placebo in one of four sequential ascending intravenous dose cohorts. All 40 participants completed the study. Seventeen (42.5%) participants experienced 22 treatment emergent adverse events (TEAEs) that were drug-related, and the rates of these TEAEs among different dose cohorts were numerically comparable. No difference was observed between the combined etesevimab group and the placebo group. The exposure after etesevimab infusion increased in an approximately proportional manner as the dose increased from 2.5 to 50 mg/kg. The elimination half-life (t1/2) value did not differ among different dose cohorts and was estimated to be around 4 weeks. Etesevimab was well tolerated after administration of a single dose at a range of 2.5 mg/kg to 50 mg/kg in healthy Chinese adults. The PK profiles of etesevimab in healthy volunteers showed typical monoclonal antibody distribution and elimination characteristics. (This study has been registered at ClinicalTrials.gov under identifier NCT04441918.)

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Characterization of neutralizing antibody with prophylactic and therapeutic efficacy against SARS-CoV-2 in rhesus monkeys

Cited by 64 publications

References 23 publications

COVA1-18 neutralizing antibody protects against SARS-CoV-2 in three preclinical models

COVA1-18 neutralizing antibody protects against SARS-CoV-2 in three preclinical models

Neutralizing Antibody Therapeutics for COVID-19

Tolerability, Safety, Pharmacokinetics, and Immunogenicity of a Novel SARS-CoV-2 Neutralizing Antibody, Etesevimab, in Chinese Healthy Adults: a Randomized, Double-Blind, Placebo-Controlled, First-in-Human Phase 1 Study

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