Neutralizing Antibody Therapeutics for COVID-19.
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ABSTRACT:
SUBMITTER: Hurt AC
PROVIDER: S-EPMC8067572 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Facing the COVID-19 global healthcare crisis, scientists worldwide are collaborating to develop prophylactic and therapeutic interventions against the disease. Antibody therapeutics hold enormous promise for the treatment of COVID-19. In March 2020, the Chinese Antibody Society, in collaboration with The Antibody Society, initiated the "COVID-19 Antibody Therapeutics Tracker" ("Tracker") (https://chineseantibody.org/covid-19-track/) program to track the antibody-based COVID-19 interventions in preclinical and clinical development globally. The data are collected from the public domain and verified by volunteers on an ongoing basis. Here, we present exploratory data analyses and visualization to demonstrate the latest trends of COVID-19 antibody development, based on data for over 150 research and development programs and molecules included in the "Tracker" as of 8 August 2020. We categorized the data mainly by their targets, formats, development status, developers and country of origin. Although details are limited in some cases, all of the anti-SARS-CoV-2 antibody candidates appear to target the viral spike protein (S protein), and most are full-length monoclonal antibodies. Most of the current COVID-19 antibody therapeutic candidates in clinical trials are repurposed drugs aimed at targets other than virus-specific proteins, while most of these virus-specific therapeutic antibodies are in discovery or preclinical studies. As of 8 August 2020, eight antibody candidates targeting the SARS-CoV-2 S protein have entered clinical studies, including LY-CoV555, REGN-COV2, JS016, TY027, CT-P59, BRII-196, BRII-198 and SCTA01. Ongoing clinical trials of SARS-CoV-2 neutralizing antibodies will help define the utility of these antibodies as a new class of therapeutics for treating COVID-19 and future coronavirus infections.
| S-EPMC7454247 | biostudies-literature
Project description:Passive transfer of antibodies from COVID-19 convalescent patients is being used as an experimental treatment for eligible patients with SARS-CoV-2 infections. The United States Food and Drug Administration's (FDA) guidelines for convalescent plasma initially recommended target antibody titers of 160. We evaluated SARS-CoV-2 neutralizing antibodies in sera from recovered COVID-19 patients using plaque reduction neutralization tests (PRNT) at moderate (PRNT50) and high (PRNT90) stringency thresholds. We found that neutralizing activity significantly increased with time post symptom onset (PSO), reaching a peak at 31-35 days PSO. At this point, the number of sera having neutralizing titers of at least 160 was ~93% (PRNT50) and ~54% (PRNT90). Sera with high SARS-CoV-2 antibody levels (>960 ELISA titers) showed maximal activity, but not all high titer sera contained neutralizing antibody at FDA recommended levels, particularly at high stringency. These results underscore the value of serum characterization for neutralization activity.
| S-EPMC7665673 | biostudies-literature
Project description:Coronavirus outbreak was declared a pandemic by World Health Organization (WHO) in March 2020. The pandemic has led to a devastating loss of life. It has shown us how infectious diseases can cause human existence at stake, and community health is important. The spike protein is the most immunogenic component of the virus. Most vaccine development strategies have focused on the receptor-binding domain (RBD) in the spike protein because it is the most specific target site that recognizes and interacts with human lung cells. Neutralizing antibodies are generated by the humoral immune system and reduce the viral load by binding to spike protein components. Neutralizing antibodies are the proteins secreted by plasma cells and serve as an important part of the defense mechanism. In the recent Covid-19 infection, neutralizing antibodies can be utilized for both diagnostic such as immune surveillance and therapeutic tools such as plasma therapy. So far, many monoclonal antibodies are in the clinical trial phase, and few of them are already in use. In this review, we have discussed details about neutralizing antibodies and their role in combating Covid-19 disease.
| S-EPMC8731133 | biostudies-literature
Project description:ImportanceEvidence on the effectiveness and safety of COVID-19 therapies across a diverse population with varied risk factors is needed to inform clinical practice.ObjectiveTo assess the safety of neutralizing monoclonal antibodies (nMAbs) for the treatment of COVID-19 and their association with adverse outcomes.Design, setting, and participantsThis retrospective cohort study included 167 183 patients from a consortium of 4 health care systems based in California, Minnesota, Texas, and Utah. The study included nonhospitalized patients 12 years and older with a positive COVID-19 laboratory test collected between November 9, 2020, and January 31, 2022, who met at least 1 emergency use authorization criterion for risk of a poor outcome.ExposureFour nMAb products (bamlanivimab, bamlanivimab-etesevimab, casirivimab-imdevimab, and sotrovimab) administered in the outpatient setting.Main outcomes and measuresClinical and SARS-CoV-2 genomic sequence data and propensity-adjusted marginal structural models were used to assess the association between treatment with nMAbs and 4 outcomes: all-cause emergency department (ED) visits, hospitalization, death, and a composite of hospitalization or death within 14 days and 30 days of the index date (defined as the date of the first positive COVID-19 test or the date of referral). Patient index dates were categorized into 4 variant epochs: pre-Delta (November 9, 2020, to June 30, 2021), Delta (July 1 to November 30, 2021), Delta and Omicron BA.1 (December 1 to 31, 2021), and Omicron BA.1 (January 1 to 31, 2022).ResultsAmong 167 183 patients, the mean (SD) age was 47.0 (18.5) years; 95 669 patients (57.2%) were female at birth, 139 379 (83.4%) were White, and 138 900 (83.1%) were non-Hispanic. A total of 25 241 patients received treatment with nMAbs. Treatment with nMAbs was associated with lower odds of ED visits within 14 days (odds ratio [OR], 0.76; 95% CI, 0.68-0.85), hospitalization within 14 days (OR, 0.52; 95% CI, 0.45-0.59), and death within 30 days (OR, 0.14; 95% CI, 0.10-0.20). The association between nMAbs and reduced risk of hospitalization was stronger in unvaccinated patients (14-day hospitalization: OR, 0.51; 95% CI, 0.44-0.59), and the associations with hospitalization and death were stronger in immunocompromised patients (hospitalization within 14 days: OR, 0.31 [95% CI, 0.24-0.41]; death within 30 days: OR, 0.13 [95% CI, 0.06-0.27]). The strength of associations of nMAbs increased incrementally among patients with a greater probability of poor outcomes; for example, the ORs for hospitalization within 14 days were 0.58 (95% CI, 0.48-0.72) among those in the third (moderate) risk stratum and 0.41 (95% CI, 0.32-0.53) among those in the fifth (highest) risk stratum. The association of nMAb treatment with reduced risk of hospitalizations within 14 days was strongest during the Delta variant epoch (OR, 0.37; 95% CI, 0.31-0.43) but not during the Omicron BA.1 epoch (OR, 1.29; 95% CI, 0.68-2.47). These findings were corroborated in the subset of patients with viral genomic data. Treatment with nMAbs was associated with a significant mortality benefit in all variant epochs (pre-Delta: OR, 0.16 [95% CI, 0.08-0.33]; Delta: OR, 0.14 [95% CI, 0.09-0.22]; Delta and Omicron BA.1: OR, 0.10 [95% CI, 0.03-0.35]; and Omicron BA.1: OR, 0.13 [95% CI, 0.02-0.93]). Potential adverse drug events were identified in 38 treated patients (0.2%).Conclusions and relevanceIn this study, nMAb treatment for COVID-19 was safe and associated with reductions in ED visits, hospitalization, and death, although it was not associated with reduced risk of hospitalization during the Omicron BA.1 epoch. These findings suggest that targeted risk stratification strategies may help optimize future nMAb treatment decisions.
| S-EPMC10126875 | biostudies-literature
Project description:Monoclonal antibodies (mAbs) with neutralizing activity against SARS-CoV-2 have demonstrated clinical benefit in cases of mild to moderate SARS-CoV-2 infection, substantially reducing the risk for hospitalization and severe disease1-4. Treatment generally requires the administration of high doses of these mAbs with limited efficacy in preventing disease complications or mortality among hospitalized COVID-19 patients5. Here we report the development and evaluation of Fc-optimized anti-SARS-CoV-2 mAbs with superior potency to prevent or treat COVID-19 disease. In several animal models of COVID-19 disease6,7, we demonstrate that selective engagement of activating FcγRs results in improved efficacy in both preventing and treating disease-induced weight loss and mortality, significantly reducing the dose required to confer full protection upon SARS-CoV-2 challenge and treatment of pre-infected animals. Our results highlight the importance of FcγR pathways in driving antibody-mediated antiviral immunity, while excluding any pathogenic or disease-enhancing effects of FcγR engagement of anti-SARS-CoV-2 antibodies upon infection. These findings have important implications for the development of Fc-engineered mAbs with optimal Fc effector function and improved clinical efficacy against COVID-19 disease.
| S-EPMC8168397 | biostudies-literature
Project description:BackgroundLY-CoV555, a neutralizing monoclonal antibody, has been associated with a decrease in viral load and the frequency of hospitalizations or emergency department visits among outpatients with coronavirus disease 2019 (Covid-19). Data are needed on the effect of this antibody in patients who are hospitalized with Covid-19.MethodsIn this platform trial of therapeutic agents, we randomly assigned hospitalized patients who had Covid-19 without end-organ failure in a 1:1 ratio to receive either LY-CoV555 or matching placebo. In addition, all the patients received high-quality supportive care as background therapy, including the antiviral drug remdesivir and, when indicated, supplemental oxygen and glucocorticoids. LY-CoV555 (at a dose of 7000 mg) or placebo was administered as a single intravenous infusion over a 1-hour period. The primary outcome was a sustained recovery during a 90-day period, as assessed in a time-to-event analysis. An interim futility assessment was performed on the basis of a seven-category ordinal scale for pulmonary function on day 5.ResultsOn October 26, 2020, the data and safety monitoring board recommended stopping enrollment for futility after 314 patients (163 in the LY-CoV555 group and 151 in the placebo group) had undergone randomization and infusion. The median interval since the onset of symptoms was 7 days (interquartile range, 5 to 9). At day 5, a total of 81 patients (50%) in the LY-CoV555 group and 81 (54%) in the placebo group were in one of the two most favorable categories of the pulmonary outcome. Across the seven categories, the odds ratio of being in a more favorable category in the LY-CoV555 group than in the placebo group was 0.85 (95% confidence interval [CI], 0.56 to 1.29; P?=?0.45). The percentage of patients with the primary safety outcome (a composite of death, serious adverse events, or clinical grade 3 or 4 adverse events through day 5) was similar in the LY-CoV555 group and the placebo group (19% and 14%, respectively; odds ratio, 1.56; 95% CI, 0.78 to 3.10; P?=?0.20). The rate ratio for a sustained recovery was 1.06 (95% CI, 0.77 to 1.47).ConclusionsMonoclonal antibody LY-CoV555, when coadministered with remdesivir, did not demonstrate efficacy among hospitalized patients who had Covid-19 without end-organ failure. (Funded by Operation Warp Speed and others; TICO ClinicalTrials.gov number, NCT04501978.).
| S-EPMC7781100 | biostudies-literature
Project description:SARS-CoV-2, the virus responsible for COVID-19, is causing a devastating worldwide pandemic, and there is a pressing need to understand the development, specificity, and neutralizing potency of humoral immune responses during acute infection. We report a cross-sectional study of antibody responses to the receptor-binding domain (RBD) of the spike protein and virus neutralization activity in a cohort of 44 hospitalized COVID-19 patients. RBD-specific IgG responses are detectable in all patients 6 days after PCR confirmation. Isotype switching to IgG occurs rapidly, primarily to IgG1 and IgG3. Using a clinical SARS-CoV-2 isolate, neutralizing antibody titers are detectable in all patients by 6 days after PCR confirmation and correlate with RBD-specific binding IgG titers. The RBD-specific binding data were further validated in a clinical setting with 231 PCR-confirmed COVID-19 patient samples. These findings have implications for understanding protective immunity against SARS-CoV-2, therapeutic use of immune plasma, and development of much-needed vaccines.
| S-EPMC7276302 | biostudies-literature
Project description:BackgroundRecent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads.MethodsIn this ongoing, double-blind, phase 1-3 trial involving nonhospitalized patients with Covid-19, we investigated two fully human, neutralizing monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, used in a combined cocktail (REGN-COV2) to reduce the risk of the emergence of treatment-resistant mutant virus. Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g of REGN-COV2, or 8.0 g of REGN-COV2 and were prospectively characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody-positive or serum antibody-negative). Key end points included the time-weighted average change in viral load from baseline (day 1) through day 7 and the percentage of patients with at least one Covid-19-related medically attended visit through day 29. Safety was assessed in all patients.ResultsData from 275 patients are reported. The least-squares mean difference (combined REGN-COV2 dose groups vs. placebo group) in the time-weighted average change in viral load from day 1 through day 7 was -0.56 log10 copies per milliliter (95% confidence interval [CI], -1.02 to -0.11) among patients who were serum antibody-negative at baseline and -0.41 log10 copies per milliliter (95% CI, -0.71 to -0.10) in the overall trial population. In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGN-COV2 dose groups reported at least one medically attended visit; among patients who were serum antibody-negative at baseline, the corresponding percentages were 15% and 6% (difference, -9 percentage points; 95% CI, -29 to 11). The percentages of patients with hypersensitivity reactions, infusion-related reactions, and other adverse events were similar in the combined REGN-COV2 dose groups and the placebo group.ConclusionsIn this interim analysis, the REGN-COV2 antibody cocktail reduced viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in the combined REGN-COV2 dose groups and the placebo group. (Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629.).
| S-EPMC7781102 | biostudies-literature
Project description:The SARS-CoV-2 virus has caused already over 3.5 million COVID-19 cases and 250,000 deaths globally. There is an urgent need to create novel models to study SARS-CoV-2 using human disease-relevant cells to understand key features of virus biology and facilitate drug screening. As primary SARS-CoV-2 infection is respiratory-based, we developed a lung organoid model using human pluripotent stem cells (hPSCs) that could be adapted for drug screens.
2020-08-11 | GSE148113 | GEO
Project description:To investigate antibody production in asymptomatic and mild COVID-19 patients. Sera from asymptomatic to severe COVID-19 patients were collected. Microneutralization (MN), fluorescence immunoassay (FIA), and enzyme-linked immunosorbent assay (ELISA) were performed. A total of 70 laboratory-confirmed COVID-19 patients were evaluated, including 15 asymptomatic/anosmia, 49 mild symptomatic, and 6 pneumonia patients. The production of the neutralizing antibody was observed in 100% of pneumonia, 93.9% of mild symptomatic, and 80.0% of asymptomatic/anosmia groups. All the patients in the pneumonia group showed high MN titer (≥1:80), while 36.7% of mild symptomatic and 20.0% of asymptomatic/anosmia groups showed high titer (p < 0.001). Anti-SARS-CoV-2 antibodies could be more sensitively detected by FIA IgG (98.8%) and ELISA (97.6%) in overall. For the FIA IgG test, all patients in the pneumonia group exhibited a high COI value (≥15.0), while 89.8% of mild symptomatic and 73.3% of asymptomatic/anosmia groups showed a high value (p = 0.049). For the ELISA test, all patients in the pneumonia group showed a high optical density (OD) ratio (≥3.0), while 65.3% of mild symptomatic and 53.3% of asymptomatic/anosmia groups showed a high ratio (p = 0.006). Most asymptomatic and mild COVID-19 patients produced the neutralizing antibody, although the titers were lower than pneumonia patients. ELISA and FIA sensitively detected anti-SARS-CoV-2 antibodies.
| S-EPMC7408950 | biostudies-literature