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Human inhalable antibody fragments neutralizing SARS-CoV-2 variants for COVID-19 therapy.

ABSTRACT: As of December 2021, coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global emergency, and novel therapeutics are urgently needed. Here we describe human single-chain variable fragment (scFv) antibodies (76clAbs) that block an epitope of the SARS-CoV-2 spike protein essential for ACE2-mediated entry into cells. 76clAbs neutralize the Delta variant and other variants being monitored (VBMs) and inhibit spike-mediated pulmonary cell-cell fusion, a critical feature of COVID-19 pathology. In two independent animal models, intranasal administration counteracted the infection. Because of their high efficiency, remarkable stability, resilience to nebulization, and low cost of production, 76clAbs may become a relevant tool for rapid, self-administrable early intervention in SARS-CoV-2-infected subjects independently of their immune status.

SUBMITTER: Minenkova O

PROVIDER: S-EPMC8837488 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Human inhalable antibody fragments neutralizing SARS-CoV-2 variants for COVID-19 therapy.

Minenkova Olga O Santapaola Daniela D Milazzo Ferdinando Maria FM Anastasi Anna Maria AM Battistuzzi Gianfranco G Chiapparino Caterina C Rosi Antonio A Gritti Giuseppe G Borleri Gianmaria G Rambaldi Alessandro A Dental Clélia C Viollet Cécile C Pagano Bruno B Salvini Laura L Marra Emanuele E Luberto Laura L Rossi Antonio A Riccio Anna A Merlo Pich Emilio E Santoro Maria Gabriella MG De Santis Rita R

Molecular therapy : the journal of the American Society of Gene Therapy 20220212 5

As of December 2021, coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global emergency, and novel therapeutics are urgently needed. Here we describe human single-chain variable fragment (scFv) antibodies (76clAbs) that block an epitope of the SARS-CoV-2 spike protein essential for ACE2-mediated entry into cells. 76clAbs neutralize the Delta variant and other variants being monitored (VBMs) and inhibit spike-mediated pulmon ...[more]

PMID: 35167974

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Project description:BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (Covid-19), which is most frequently mild yet can be severe and life-threatening. Virus-neutralizing monoclonal antibodies are predicted to reduce viral load, ameliorate symptoms, and prevent hospitalization.MethodsIn this ongoing phase 2 trial involving outpatients with recently diagnosed mild or moderate Covid-19, we randomly assigned 452 patients to receive a single intravenous infusion of neutralizing antibody LY-CoV555 in one of three doses (700 mg, 2800 mg, or 7000 mg) or placebo and evaluated the quantitative virologic end points and clinical outcomes. The primary outcome was the change from baseline in the viral load at day 11. The results of a preplanned interim analysis as of September 5, 2020, are reported here.ResultsAt the time of the interim analysis, the observed mean decrease from baseline in the log viral load for the entire population was -3.81, for an elimination of more than 99.97% of viral RNA. For patients who received the 2800-mg dose of LY-CoV555, the difference from placebo in the decrease from baseline was -0.53 (95% confidence interval [CI], -0.98 to -0.08; P = 0.02), for a viral load that was lower by a factor of 3.4. Smaller differences from placebo in the change from baseline were observed among the patients who received the 700-mg dose (-0.20; 95% CI, -0.66 to 0.25; P = 0.38) or the 7000-mg dose (0.09; 95% CI, -0.37 to 0.55; P = 0.70). On days 2 to 6, the patients who received LY-CoV555 had a slightly lower severity of symptoms than those who received placebo. The percentage of patients who had a Covid-19-related hospitalization or visit to an emergency department was 1.6% in the LY-CoV555 group and 6.3% in the placebo group.ConclusionsIn this interim analysis of a phase 2 trial, one of three doses of neutralizing antibody LY-CoV555 appeared to accelerate the natural decline in viral load over time, whereas the other doses had not by day 11. (Funded by Eli Lilly; BLAZE-1 ClinicalTrials.gov number, NCT04427501.).

Project description:The comprehensive knowledge regarding the immune response during coronavirus disease 2019 (COVID-19) vaccination is limited. The aim of this study was to longitudinally investigate not only the dynamic changes of peripheral lymphocyte subpopulations and cytokine levels but parallel changes of antibody levels against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Blood samples of 20 healthcare workers with two doses of COVID-19 vaccine were prospectively collected. The percentages of lymphocyte subpopulations from peripheral blood and cytokine production in lymphocytes with in vitro stimulation were assessed using eight-color flow cytometry. SARS-CoV-2 spike antibodies (anti-S Abs) and functional neutralizing antibodies (nAbs) were also measured. The relation between pre- and post-vaccination immunity was analyzed. There are 7 men and 13 women with a median age of 44.0 years (range: 25.7-59.5 years). The individuals had an increased percentage of lymphocytes at post-vaccination with statistical significance post first dose (p = 0.031). The levels of transitional cells (p = 0.001), such as plasmablasts (p < 0.001) and plasma cells (p = 0.031), were increased compared with pre-vaccination. Recent thymic emigrants of CD4+ T cells subsets were significantly higher at post-vaccination than those at pre-vaccination (p = 0.029). Intracellular levels of tumor necrosis factor-alpha, interferon-γ, interleukin (IL)-2, IL-21, transforming growth factor-beta and IL-17 produced by CD4+ T, CD8+ T, and natural killer cells were increased. All individual samples showed reactivity to anti-S Abs and the levels of nAbs were elevated after vaccination. The magnitude of adaptive immunity was associated with vaccine types and doses. Alterations of total memory B cells (p < 0.001), non-switched memory B cells (p = 0.016), and memory Treg cells (p < 0.001) were independent predictors for nAb levels. These findings might be helpful in elucidating the immune response of COVID-19 vaccination and in developing new strategies for immunization.

Dataset Information

Human inhalable antibody fragments neutralizing SARS-CoV-2 variants for COVID-19 therapy.

Publications

Human inhalable antibody fragments neutralizing SARS-CoV-2 variants for COVID-19 therapy.

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