6 research outputs found
The monoclonal antibody combination REGEN-COV protects against SARS-CoV-2 mutational escape in preclinical and human studies.
Monoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. Because rapidly emerging virus mutants are becoming the next major concern in the fight against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment-induced emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of virus variants in SARS-COV-2 isolates found in COVID-19 patients treated with the two-antibody combination REGEN-COV, as well as in preclinical in vitro studies using single, dual, or triple antibody combinations, and in hamster in vivo studies using REGEN-COV or single monoclonal antibody treatments. Our study demonstrates that the combination of non-competing antibodies in REGEN-COV provides protection against all current SARS-CoV-2 variants of concern/interest and also protects against emergence of new variants and their potential seeding into the population in a clinical setting
Effect of Subcutaneous Casirivimab and Imdevimab Antibody Combination vs Placebo on Development of Symptomatic COVID-19 in Early Asymptomatic SARS-CoV-2 Infection: A Randomized Clinical Trial
Importance: Easy-to-administer anti-SARS-CoV-2 treatments may be used to prevent progression from asymptomatic infection to symptomatic disease and to reduce viral carriage. Objective: To evaluate the effect of combination subcutaneous casirivimab and imdevimab on progression from early asymptomatic SARS-CoV-2 infection to symptomatic COVID-19. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 3 trial of close household contacts of a SARS-CoV-2-infected index case at 112 sites in the US, Romania, and Moldova enrolled July 13, 2020-January 28, 2021; follow-up ended March 11, 2021. Asymptomatic individuals (aged ≥12 years) were eligible if identified within 96 hours of index case positive test collection. Results from 314 individuals positive on SARS-CoV-2 reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) testing are reported. Interventions: Individuals were randomized 1:1 to receive 1 dose of subcutaneous casirivimab and imdevimab, 1200 mg (600 mg of each; n = 158), or placebo (n = 156). Main Outcomes and Measures: The primary end point was the proportion of seronegative participants who developed symptomatic COVID-19 during the 28-day efficacy assessment period. The key secondary efficacy end points were the number of weeks of symptomatic SARS-CoV-2 infection and the number of weeks of high viral load (>4 log10copies/mL). Results: Among 314 randomized participants (mean age, 41.0 years; 51.6% women), 310 (99.7%) completed the efficacy assessment period; 204 were asymptomatic and seronegative at baseline and included in the primary efficacy analysis. Subcutaneous casirivimab and imdevimab, 1200 mg, significantly prevented progression to symptomatic disease (29/100 [29.0%] vs 44/104 [42.3%] with placebo; odds ratio, 0.54 [95% CI, 0.30-0.97]; P =.04; absolute risk difference, -13.3% [95% CI, -26.3% to -0.3%]). Casirivimab and imdevimab reduced the number of symptomatic weeks per 1000 participants (895.7 weeks vs 1637.4 weeks with placebo; P =.03), an approximately 5.6-day reduction in symptom duration per symptomatic participant. Treatment with casirivimab and imdevimab also reduced the number of high viral load weeks per 1000 participants (489.8 weeks vs 811.9 weeks with placebo; P =.001). The proportion of participants receiving casirivimab and imdevimab who had 1 or more treatment-emergent adverse event was 33.5% vs 48.1% for placebo, including events related (25.8% vs 39.7%) or not related (11.0% vs 16.0%) to COVID-19. Conclusions and Relevance: Among asymptomatic SARS-CoV-2 RT-qPCR-positive individuals living with an infected household contact, treatment with subcutaneous casirivimab and imdevimab antibody combination vs placebo significantly reduced the incidence of symptomatic COVID-19 over 28 days. Trial Registration: ClinicalTrials.gov Identifier: NCT04452318
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Differentiation and transformation of neural plate cells
The developmental potential of presumptive neural plate cells of prestreak chick embryos (stage 1) and neural plate cells from definitive streak chick embryos (stage 4) has been examined in cell culture using specific markers that identify the major cell types in the vertebrate central nervous system. The prestreak presumptive neural plate (PSPNP) cells, stage 1, assume an epithelial appearance
in vitro and synthesize cellular fibronectin, but do not express markers for the neuronal, astrocytic, melanocytic, or oligodendrocytic lineages. Conversely, definitive-streak neural plate (DSNP) cells contain precursors which express cell-type-specific markers for terminally differentiated neurons, astrocytes, and melanocytes, and synthesize an extracellular matrix of cellular fibronectin. Differentiation of DSNP cells
in vitro can be prevented by infection with a temperature-sensitive mutant of Rous sarcoma virus (RSV),
tsNY68. Differentiation of DSNP cell transformants can be resumed by a temperature shift to the nonpermissive temperature. The morphological and biochemical changes associated with
tsNY68 transformation are accompanied by alterations in pp60
src
kinase activity in the transformed cells
Isolation of the chicken thymidine kinase gene by plasmid rescue
The bacterial plasmid pBR322 was used as a vehicle to isolate genes coding for selectable markers from higher eukaryotes. The chicken thymidine kinase (tk) gene was obtained as a 2.2-kilobase EcoRI/HindIII insert in pBR322. The cloned gene transforms tk- animal cells with an efficiency equal to that of the cloned herpes simplex virus-1 tk gene