Monoclonal Antibodies with Extended Half-Life to Prevent Covid-19.
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ABSTRACT:
SUBMITTER: Abraham J
PROVIDER: S-EPMC9202318 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
Publications
Monoclonal Antibodies with Extended Half-Life to Prevent Covid-19.
The New England journal of medicine 20220601 23
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Project description:BackgroundRespiratory syncytial virus (RSV) is one of the most important respiratory pathogens in young children. Infants <6 months of age and infants and young children with extreme pre-term birth, and cardiac and pulmonary co-morbidities experience the highest incidence of severe RSV disease. There are no licensed vaccines; immunoprophylaxis is recommended for the highest risk children. Extended half-life RSV monoclonal antibodies (EHL-mAbs) are under development intended for immunization of all infants and high-risk children <2 years of age. We modeled the anticipated public health benefits of RSV EHL-mAb immunization using the number needed to immunize (NNI).MethodsWe combined RSV hospitalization, outpatient and outpatient lower respiratory tract infection (LRI) incidence estimates and a range of immunization efficacies to estimate the annual NNI. We calculated the absolute incidence rate reduction (ARR) by multiplying the incidence rates by immunization efficacy. NNI was calculated as the reciprocal of the ARR.ResultsFor an RSV EHL-mAb with 70% efficacy, 6-18 infants would need to be immunized to prevent one RSV-associated outpatient visit, and 13-33 infants would need to be immunized to prevent one RSV-associated LRI outpatient visit. To prevent one RSV-associated hospitalization, 37-85 infants 0-5 months of age, and 107-280 infants 6-11 months of age would need to be immunized.ConclusionsPublic health benefits, such as disease cases averted due to immunization, are essential elements in consideration of candidate vaccines for a national immunization program. An RSV EHL-mAb of moderate efficacy could have high impact. These data provide an additional perspective for public health decision making.
| S-EPMC8684408 | biostudies-literature
Project description:Several vaccines and extended half-life monoclonal antibodies (mAbs) against respiratory syncytial virus (RSV) have shown promise in clinical trials. We used age-structured transmission models to predict the possible impact of various RSV prevention strategies including maternal immunization, live-attenuated vaccines, and long-lasting mAbs. Our results suggest that maternal immunization and long-lasting mAbs are likely to be highly effective in preventing RSV hospitalizations in infants under 6 months of age, averting more than half of RSV hospitalizations in neonates. Live-attenuated vaccines could reduce RSV hospitalizations in vaccinated age groups and are also predicted to have a modest effect in unvaccinated age groups because of disruptions to transmission. Compared to year-round vaccination, a seasonal vaccination program at the country level provides at most a minor advantage regarding efficiency. Our findings highlight the substantial public health impact that upcoming RSV prevention strategies may provide.
| S-EPMC9612629 | biostudies-literature
Project description:BackgroundFerrets have long been used as a disease model for the study of influenza vaccines, but a more recent use has been for the study of human monoclonal antibodies directed against influenza viruses. Published data suggest that human antibodies are cleared unusually quickly from the ferret and that immune responses may be partially responsible. This immunogenicity increases variability within groups and may present an obstacle to long-term studies.ObjectiveOur aim was to identify an antibody design with reduced immunogenicity and longer circulating half-life in ferrets.MethodsThe constant region coding sequences for ferret immunoglobulin G were cloned, and chimeric human/ferret antibodies were expressed and purified. Some of the chimeric antibodies included substitutions that have been shown to extend the half-life of human IgG antibodies. These chimeric antibodies were tested for binding to recombinant ferret FcRn receptor and then evaluated in pharmacokinetic studies in ferrets.ResultsA one-residue substitution in the ferret Fc domain, S252Y, was identified that increased binding affinity to the ferret neonatal receptor by 24-fold and extended half-life from 65 ± 27 to 206 ± 28 hours or ~9 days. Ferrets dosed twice with this surrogate antibody showed no indications of an immune response.ConclusionExpressing the variable region of a candidate human therapeutic antibody with ferret constant regions containing the S252Y substitution can offer long half-life and limit immunogenicity.
| S-EPMC4181826 | biostudies-literature
Project description:Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effectiveness and safety of SARS‐CoV‐2‐neutralising mAbs, including mAb fragments, to prevent infection with SARS‐CoV‐2 causing COVID‐19; and to maintain the currency of the evidence, using a living systematic review approach.
| S-EPMC8135631 | biostudies-literature
Project description: Not available
| S-EPMC9205158 | biostudies-literature
Project description: Not available
| S-EPMC8646454 | biostudies-literature
Project description:Increasing evidence suggests that signaling through the prolactin/prolactin receptor axis is important for stimulation the growth of many cancers including glioblastoma multiforme, breast and ovarian carcinoma. Efficient inhibitors of signaling have previously been developed but their applicability as cancer drugs is limited by the short in vivo half-life. In this study, we show that a fusion protein, consisting of the prolactin receptor antagonist PrlRA and an albumin binding domain for half-life extension can be expressed as inclusion bodies in Escherichia coli and efficiently refolded and purified to homogeneity. The fusion protein was found to have strong affinity for the two intended targets: the prolactin receptor (KD = 2.3±0.2 nM) and mouse serum albumin (KD = 0.38±0.01 nM). Further investigation showed that it could efficiently prevent prolactin mediated phosphorylation of STAT5 at 100 nM concentration and above, similar to the PrlRA itself, suggesting a potential as drug for cancer therapy in the future. Complexion with HSA weakened the affinity for the receptor to 21±3 nM, however the ability to prevent phosphorylation of STAT5 was still prominent. Injection into rats showed a 100-fold higher concentration in blood after 24 h compared to PrlRA itself.
| S-EPMC6504076 | biostudies-literature
Project description:BackgroundAZD7442 is a combination of extended half-life, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific neutralizing monoclonal antibodies (tixagevimab and cilgavimab).MethodsThis phase 1, first-in-human, randomized, double-blind, placebo-controlled, dose-escalation study evaluated AZD7442 administered intramuscularly (300 mg) or intravenously (300, 1000, or 3000 mg) in healthy adults (aged 18-55 years). The primary end point was safety and tolerability. Secondary end points included pharmacokinetics and antidrug antibodies.ResultsBetween 18 August and 16 October 2020, a total of 60 participants were enrolled; 50 received AZD7442, and 10 received placebo. Adverse events (all of mild or moderate intensity) occurred in 26 participants (52.0%) in the AZD7442 groups and 8 (80.0%) in the placebo group. No infusion or injection site or hypersensitivity reactions occurred. Tixagevimab and cilgavimab had mean half-lives of approximately 90 days (range, 87.0-95.3 days for tixagevimab and 79.8--91.1 days for cilgavimab) and similar pharmacokinetic profiles over the 361-day study period. SARS-CoV-2-specific neutralizing antibody titers provided by AZD7442 were maintained above those in plasma from convalescent patients with coronavirus disease 2019 (COVID-19).ConclusionsAZD7442 was well tolerated in healthy adults, showing a favorable safety profile across all doses. Depending on the SARS-CoV-2 variant, pharmacokinetic analyses suggest the AZD7442 could offer protection for ≥6 months against symptomatic COVID-19 after a single 300-mg intramuscular administration.Clinical trials registrationNCT04507256.
| S-EPMC10175065 | biostudies-literature
Project description:ObjectiveMonoclonal antibodies (mAbs) against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) reduced Coronavirus Disease 2019 (COVID-19) hospitalizations in people at risk of clinical worsening. Real-world descriptions are limited.MethodsCONDIVIDIAMO, a two-year multicenter observational study, consecutively enrolled SARS-CoV-2 outpatients with ≥1 risk factor for COVID-19 progression receiving mAbs. Demographic data, underlying medical condition, type of mAbs combination received, duration of symptoms before mAbs administration, COVID-19 vaccination history, were collected upon enrolment and centrally recorded. Data on outcomes (hospitalizations, reasons of hospitalization, deaths) were prospectively collected. The primary endpoint was the rate of hospitalization or death in a 28-day follow-up, whichever occurred first; subjects were censored at the day of last follow-up or up to 28 days. The Kaplan-Meier method was used to estimate the incidence rate curve in time. The Cox regression model was used to assess potential risk factors for unfavorable outcome. Results were shown as hazard ratio (HR) along with the corresponding 95 % Confidence Interval (95%CI).ResultsAmong 1534 subjects (median [interquartile range, IQR] age 66.5 [52.4-74.9] years, 693 [45.2 %] women), 632 (41.2 %) received bamlanivimab ± etesevimab, 209 (13.6 %) casirivimab/imdevimab, 586 (38.2 %) sotrovimab, 107 (7.0 %) tixagevimab/cilgavimab. After 28-day follow-up, 87/1534 (5.6 %, 95%CI: 4.4%-6.8 %) met the primary outcome (85 hospitalizations, 2 deaths). Hospitalizations for COVID-19 (52, 3.4 %) occurred earlier than for other reasons (33, 2.1 %), after a median (IQR) of 3.5 (1-7) versus 8 (3-15) days (p = 0.006) from mAbs administration.In a multivariable Cox regression model, factors independently associated with increased hospitalization risk were age (hazard ratio [HR] 1.02, 95%CI 1.00-1.03, p = 0.021), immunodeficiency (HR 1.78, 95%CI 1.11-2.85, p = 0.017), pre-Omicron calendar period (HR 1.66, 95%CI 1.02-2.69, p = 0.041).ConclusionsMAbs real-world data over a 2-year changing pandemic landscape showed the feasibility of the intervention, although the hospitalization rate was not negligible. Immunosuppressed subjects remain more at risk of clinical worsening.
| S-EPMC11378919 | biostudies-literature
Project description: Not available
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