scholarly journals 1088. A Whole-Body Quantitative System Pharmacology Physiologically-Based Pharmacokinetic (QSP/PBPK) Model to Support Dose Selection of ADG20: an Extended Half-Life Monoclonal Antibody Being Developed for the Treatment of Coronavirus Disease (COVID-19)

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S635-S635
Author(s):  
Evan D Tarbell ◽  
Scott A Van Wart ◽  
Dhaval K Shah ◽  
Laura M Walker ◽  
Andrew Santulli ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Viral Load ◽  
Half Life ◽  
Time Course ◽  
Pbpk Model ◽  
Growth Suppression ◽  
Dose Selection ◽  
Independent Contractor ◽  
Viral Growth

Abstract Background ADG20 is a fully human IgG1 monoclonal antibody engineered to have potent and broad neutralization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-like CoVs with pandemic potential and an extended half-life. ADG20 is administered intramuscularly (IM). A QSP/PBPK model was constructed to support dose selection for a Phase 2/3 trial of ambulatory patients with mild to moderate COVID-19 (STAMP: NCT04805671). Methods A QSP/PBPK model was used to simulate receptor occupancy (RO) and drug exposure in the upper airway (nasopharyngeal/oropharyngeal epithelial lining fluid [ELF] compartment). RO was linked to an existing viral dynamic model to enable the prediction of the natural time course of viral load and the effect of ADG20 on viral clearance and infectivity rate. RO was calculated using: 1) in vitro ADG20–SARS-CoV-2 binding kinetics (association rate constant (kon) of 1.52E+06 M-1•s1 and dissociation rate constant (koff) of 2.81E-04 s-1 from a Biacore assay; 2) time course of ADG20 concentrations in ELF; and 3) time course of viral load following ADG20 administration. Molar SARS-CoV-2 viral binding site capacity was calculated assuming 40 spike proteins per virion, 3 binding sites per spike, and an initial viral load of log 107 copies/mL for all patients. The QSP/PBPK model and a 2018 CDC reference body weight distribution (45–150 kg) were used to simulate 1000 concentration-time profiles for a range of candidate ADG20 regimens. ADG20 regimens were evaluated against 2 criteria: 1) ability to attain near complete ( >90%), and durable (28-day) SARS-CoV-2 RO in the ELF; and 2) ability to maintain ELF ADG20 concentrations relative to a concentration (0.5 mg/L) associated with 100% viral growth suppression in an in vitro post-infection assay. Results A single 300 mg IM ADG20 dose met the dose selection criteria in terms of RO (Figure A) and viral growth suppression (Figure B). Conclusion These data support the evaluation of an ADG20 300 mg IM dose for the treatment of mild to moderate COVID-19. ADG20 is forecasted to attain near complete ( >90%) SARS-CoV-2 RO in the ELF and maintain ELF ADG20 concentrations above that associated with 100% viral growth suppression in vitro. Figure. QSP/PBPK model forecast of ADG20 300 mg IM in adults (A) Predicted RO expressed as percent occupancy with the dotted line representing the threshold for 90% RO. (B) Predicted median concentration of ADG20 relative to a concentration (0.5 mg/L) associated with 100% viral growth suppression as indicated by the dotted line; the shaded area represents the 90% prediction interval. Disclosures Evan D. Tarbell, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Scott A. Van Wart, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Laura M. Walker, PhD, Adagio Therapeutics, Inc. (Other Financial or Material Support, Laura M. Walker is an inventor on a patent application submitted by Adagio Therapeutics, Inc., describing the engineered SARS-CoV-2 antibody.) Andrew Santulli, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Lynn E. Connolly, MD, PhD, Adagio Therapeutics, Inc. (Employee) Donald E Mager, PharmD, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Paul G. Ambrose, PharmD, Adagio Therapeutics, Inc. (Employee)

scholarly journals 1089. Use of a Whole-Body Quantitative System Pharmacology Physiologically-Based Pharmacokinetic (QSP/PBPK) Model to Support Dose Selection of ADG20: an Extended Half-Life Monoclonal Antibody Being Developed for the Prevention of Coronavirus Disease (COVID-19)

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S635-S636
Author(s):  
Scott A Van Wart ◽  
Evan D Tarbell ◽  
Kristin Narayan ◽  
Laura M Walker ◽  
Lynn E Connolly ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Weight Distribution ◽  
Half Life ◽  
Pbpk Model ◽  
Whole Body ◽  
Transfer Model ◽  
Serum Concentrations ◽  
Dose Selection ◽  
Independent Contractor

Abstract Background ADG20 is a fully human IgG1 monoclonal antibody engineered to have potent and broad neutralization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-like CoVs with pandemic potential as well as an extended-half-life. ADG20 is administered intramuscularly (IM). A QSP/PBPK model was constructed to support dose selection for a COVID-19 Phase 2/3 prevention trial (EVADE: NCT04859517). Methods A QSP/PBPK model and a CDC reference adult body weight distribution (45–150 kg) were used to simulate 1000 concentration-time profiles for candidate single-dose regimens of ADG20 (150–450 mg IM). As serum virus neutralizing antibody (sVNA) titers are reportedly a key correlate of protection from COVID-19, a regression equation between time-matched serum ADG20 concentrations (following a 300 mg IM dose) and sVNA titers was developed using measured titers against authentic SARS-CoV-2 determined by a plaque reduction neutralization assay. Projected ADG20 serum concentrations relative to neutralization potency in vitro (90% inhibitory concentration [IC90]) for authentic SARS-CoV-2 were also evaluated. Results The measured 50% neutralization titer (MN50; geometric mean [coefficient of variation, %]) was 1382 (32.7%) 13 days after a single 300 mg IM dose of ADG20. This was within the range of peak sVNA titers reported for COVID-19 vaccine recipients. Using the linear equation relating serum ADG20 concentration to time matched individual MN50 titers and the QSP/PBPK median PK prediction, the anticipated median MN50 exceeded the threshold for protection from SARS-CoV-2 infection established in a non-human primate adoptive transfer model for up to 52 weeks. Based on the QSP/PBPK median PK prediction, median ADG20 serum concentrations are projected to remain >100-fold above the ADG20 IC90 value of 0.011 mg/L against authentic SARS-CoV-2 for up to 52 weeks (Figure). Conclusion Following administration of a single 300 mg IM dose, sVNA titers and concentrations of ADG20 are projected to remain above thresholds anticipated to be required for protection against COVID-19 for up to 52 weeks. These data support the evaluation of a single ADG20 300 mg IM dose for the prevention of COVID-19. Figure. QSP/PBPK model forecast of ADG20 300 mg IM in adults. Predicted median serum ADG20 concentration is shown with the dotted line representing 100× in vitro IC90 of 0.011 mg/L or 1.1 mg/L; the solid black line represents the simulated median; the shaded area represents the 90% prediction interval. The predicted median half-life of ADG20 300 mg IM exceeded 74 days. PBPK model inputs include Ln-normal Kd,FcRn of 9.55 nM (10% IIV); IM bioavailability of 100%; 15% IIV on muscle lymph RC; and Centers for Disease Control and Prevention weight distribution of 45–150 kg. FcRn, neonatal Fc receptor; IIV, inter-individual variability; Kd, dissociation constant; Ln, log-normal; RC, reflection coefficient. Disclosures Scott A. Van Wart, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Evan D. Tarbell, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Kristin Narayan, PhD, Adagio Therapeutics, Inc. (Employee) Laura M. Walker, PhD, Adagio Therapeutics, Inc. (Other Financial or Material Support, Laura M. Walker is an inventor on a patent application submitted by Adagio Therapeutics, Inc., describing the engineered SARS-CoV-2 antibody.) Lynn E. Connolly, MD, PhD, Adagio Therapeutics, Inc. (Employee) Paul G. Ambrose, PharmD, Adagio Therapeutics, Inc. (Employee)

scholarly journals Quantification system for the viral dynamics of a highly pathogenic simian/human immunodeficiency virus based on an in vitroexperiment and a mathematical model

2021 ◽  
Author(s):  
Shingo Iwami ◽  
Benjamin P Holder ◽  
Catherine A. A. Beauchemin ◽  
Satoru Morita ◽  
Tetsuko Tada ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Cell Culture ◽  
Viral Load ◽  
Half Life ◽  
Time Course ◽  
Basic Reproductive Number ◽  
Reproductive Number ◽  
F Cells ◽  
Shiv Infection

Background Developing a quantitative understanding of viral kinetics is useful for determining the pathogenesis and transmissibility of the virus, predicting the course of disease, and evaluating the effects of antiviral therapy. The availability of data in clinical, animal, and cell culture studies, however, has been quite limited. Many studies of virus infection kinetics have been based solely on measures of total or infectious virus count. Here, we introduce a new mathematical model which tracks both infectious and total viral load, as well as the fraction of infected and uninfected cells within a cell culture, and apply it to analyze time-course data of an SHIV infection in vitro. Results We infected HSC-F cells with SHIV-KS661 and measured the concentration of Nef-negative (target) and Nef-positive (infected) HSC-F cells, the total viral load, and the infectious viral load daily for nine days. The experiments were repeated at four different MOIs, and the model was fitted to the full dataset simultaneously. Our analysis allowed us to extract an infected cell half-life of 14.1 h, a half-life of SHIV-KS661 infectiousness of 17.9 h, a virus burst size of 22.1 thousand RNA copies or 0.19 TCID50, and a basic reproductive number of 62.8. Furthermore, we calculated that SHIV-KS661 virus-infected cells produce at least 1 infectious virion for every 350 virions produced. Conclusions Our method, combining in vitro experiments and a mathematical model, provides detailed quantitative insights into the kinetics of the SHIV infection which could be used to significantly improve the understanding of SHIV and HIV-1 pathogenesis. The method could also be applied to other viral infections and used to improve the in vitro determination of the effect and efficacy of antiviral compounds.

scholarly journals Quantification system for the viral dynamics of a highly pathogenic simian/human immunodeficiency virus based on an in vitro experiment and a mathematical model

2021 ◽  
Author(s):  
Shingo Iwami ◽  
Benjamin P Holder ◽  
Catherine A. A. Beauchemin ◽  
Satoru Morita ◽  
Tetsuko Tada ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Cell Culture ◽  
Viral Load ◽  
Half Life ◽  
Time Course ◽  
Basic Reproductive Number ◽  
Reproductive Number ◽  
F Cells ◽  
Shiv Infection

Background Developing a quantitative understanding of viral kinetics is useful for determining the pathogenesis and transmissibility of the virus, predicting the course of disease, and evaluating the effects of antiviral therapy. The availability of data in clinical, animal, and cell culture studies, however, has been quite limited. Many studies of virus infection kinetics have been based solely on measures of total or infectious virus count. Here, we introduce a new mathematical model which tracks both infectious and total viral load, as well as the fraction of infected and uninfected cells within a cell culture, and apply it to analyze time-course data of an SHIV infection in vitro. Results We infected HSC-F cells with SHIV-KS661 and measured the concentration of Nef-negative (target) and Nef-positive (infected) HSC-F cells, the total viral load, and the infectious viral load daily for nine days. The experiments were repeated at four different MOIs, and the model was fitted to the full dataset simultaneously. Our analysis allowed us to extract an infected cell half-life of 14.1 h, a half-life of SHIV-KS661 infectiousness of 17.9 h, a virus burst size of 22.1 thousand RNA copies or 0.19 TCID50, and a basic reproductive number of 62.8. Furthermore, we calculated that SHIV-KS661 virus-infected cells produce at least 1 infectious virion for every 350 virions produced. Conclusions Our method, combining in vitro experiments and a mathematical model, provides detailed quantitative insights into the kinetics of the SHIV infection which could be used to significantly improve the understanding of SHIV and HIV-1 pathogenesis. The method could also be applied to other viral infections and used to improve the in vitro determination of the effect and efficacy of antiviral compounds.

scholarly journals Quantification system for the viral dynamics of a highly pathogenic simian/human immunodeficiency virus based on an in vitroexperiment and a mathematical model

2021 ◽  
Author(s):  
Shingo Iwami ◽  
Benjamin P Holder ◽  
Catherine A. A. Beauchemin ◽  
Satoru Morita ◽  
Tetsuko Tada ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Cell Culture ◽  
Viral Load ◽  
Half Life ◽  
Time Course ◽  
Basic Reproductive Number ◽  
Reproductive Number ◽  
F Cells ◽  
Shiv Infection

Background Developing a quantitative understanding of viral kinetics is useful for determining the pathogenesis and transmissibility of the virus, predicting the course of disease, and evaluating the effects of antiviral therapy. The availability of data in clinical, animal, and cell culture studies, however, has been quite limited. Many studies of virus infection kinetics have been based solely on measures of total or infectious virus count. Here, we introduce a new mathematical model which tracks both infectious and total viral load, as well as the fraction of infected and uninfected cells within a cell culture, and apply it to analyze time-course data of an SHIV infection in vitro. Results We infected HSC-F cells with SHIV-KS661 and measured the concentration of Nef-negative (target) and Nef-positive (infected) HSC-F cells, the total viral load, and the infectious viral load daily for nine days. The experiments were repeated at four different MOIs, and the model was fitted to the full dataset simultaneously. Our analysis allowed us to extract an infected cell half-life of 14.1 h, a half-life of SHIV-KS661 infectiousness of 17.9 h, a virus burst size of 22.1 thousand RNA copies or 0.19 TCID50, and a basic reproductive number of 62.8. Furthermore, we calculated that SHIV-KS661 virus-infected cells produce at least 1 infectious virion for every 350 virions produced. Conclusions Our method, combining in vitro experiments and a mathematical model, provides detailed quantitative insights into the kinetics of the SHIV infection which could be used to significantly improve the understanding of SHIV and HIV-1 pathogenesis. The method could also be applied to other viral infections and used to improve the in vitro determination of the effect and efficacy of antiviral compounds.

Glucocorticoids regulate NHE-3 transcription in OKP cells

1996 ◽  
Vol 270 (1) ◽  
pp. F164-F169 ◽  
Author(s):  
M. Baum ◽  
M. Amemiya ◽  
V. Dwarakanath ◽  
R. J. Alpern ◽  
O. W. Moe
Keyword(s):  
Gene Transcription ◽  
Half Life ◽  
Time Course ◽  
In Vitro Transcription ◽  
Mrna Abundance ◽  
Proton Secretion ◽  
Threefold Increase ◽  
Mrna Half Life ◽  
Synthetic Glucocorticoid

OKP cells express NHE-3, an amiloride-resistant Na+/H+ antiporter, which is likely an isoform responsible for apical proton secretion by the proximal tubule. We have previously shown that an amiloride-resistant Na+/H+ antiporter in OKP cells is regulated by dexamethasone, a synthetic glucocorticoid. The purpose of the present study was to examine the mechanism for the glucocorticoid-mediated increase in Na+/H+ antiporter activity. Incubation of OKP cells with 10(-6) M dexamethasone resulted in a two- to threefold increase in NHE-3 mRNA abundance. This increase was seen after 4 h of incubation with dexamethasone, a time course similar to that found for Na+/H+ antiporter activity. To examine the mechanism for the increase in NHE-3 mRNA abundance, mRNA half-life and in vitro transcription experiments were performed. NHE-3 mRNA had a half-life of 8 h in control and dexamethasone-treated cells. The rate of in vitro transcription was 1.8-fold greater when OKP cells were treated with dexamethasone. These data suggest that the glucocorticoid-mediated increase in Na+/H+ antiporter activity is due to an increase in NHE-3 gene transcription.

scholarly journals AUG-3387, a Human-Derived Monoclonal Antibody Neutralizes SARS-CoV-2 Variants and Reduces Viral Load from Therapeutic Treatment of Hamsters In Vivo

2021 ◽  
Author(s):  
Christopher J Emig ◽  
Marco A Mena ◽  
Steven J Henry ◽  
Adela Vitug ◽  
Christian John Ventura ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Viral Load ◽  
Human Monoclonal Antibody ◽  
Dry Powder Inhaler ◽  
Spike Protein ◽  
Geometric Standard Deviation ◽  
Human Populations ◽  
Dry Powder ◽  
Powder Formulation

Infections from the SARS-CoV-2 virus have killed over 4.6 million people since it began spreading through human populations in late 2019. In order to develop a therapeutic or prophylactic antibody to help mitigate the effects of the pandemic, a human monoclonal antibody (mAb) that binds to the SARS-CoV-2 spike protein was isolated from a convalescent patient following recovery from COVID-19 disease. This mAb, designated AUG-3387, demonstrates a high affinity for the spike protein of the original viral strains and all variants tested to date. In vitro pseudovirus neutralization and SARS-CoV-2 neutralization activity has been demonstrated in vitro. In addition, a dry powder formulation has been prepared using a Thin Film Freezing (TFF) process that exhibited a fine particle fraction (FPF) of 50.95 ± 7.69% and a mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of 3.74 ± 0.73 μm and 2.73 ± 0.20, respectively. The dry powder is suitable for delivery directly to the lungs of infected patients using a dry powder inhaler device. Importantly, AUG-3387, administered as a liquid by intraperitoneal injection or the dry powder formulation delivered intratracheally into Syrian hamsters 24 hours after intranasal SARS-CoV-2 infection, demonstrated a dose-dependent reduction in the lung viral load of the virus. These data suggest that AUG-3387 formulated as a dry powder demonstrates potential to treat COVID-19.

Phase I Clinical Trial of a Novel, Long-Acting Antithrombotic Drug: A Human Monoclonal Antibody Partially Inhibiting FVIII Activity.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 312-312 ◽  
Author(s):  
Peter Verhamme ◽  
Steve Pakola ◽  
Marc Jacquemin ◽  
Jean Marie Saint-Remy ◽  
Jean Marie Stassen ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Half Life ◽  
Human Monoclonal Antibody ◽  
Older Age ◽  
Dose Escalation Study ◽  
Double Blind ◽  
Age Cohorts ◽  
Pharmacodynamic Profile

Abstract Current treatments for preventing thrombotic disease are still inconvenient and associated with a high risk of bleeding. Improved anticoagulant agents are therefore required. TB-402 is a monoclonal antibody (fully human IgG4-antibody) that targets factor VIII (FVIII) and represents a novel type of anticoagulant agent. In vitro, TB-402 only partially inhibits human FVIII even when TB-402 is in excess over FVIII. Preclinical studies confirmed this plateau inhibition and also established the antithrombotic efficacy of TB-402 (Jacquemin M, et al. J Thromb Haemost.2006; 4:1047). Plateau inhibition even in setting of excess TB-402 may allow for improved safety with decreased risk of overdose and decreased need for monitoring. The long half-life of the antibody creates the possibility for a once a month administration. TB-402 may therefore represent a safer and more convenient agent than other available anticoagulants. A Phase I study has completed enrolment of 56 healthy male volunteers. This randomised, double-blind, placebo-controlled, single dose, dose escalation study evaluated the safety and the pharmacokinetic/pharmacodynamic profile of TB-402. Volunteers were treated with a single intravenous administration of placebo or TB-402 at doses of 0.015, 0.1, 0.5, 2.5, 12.5, 37.5, 188, 620 or 1,860 μg/kg. All doses were evaluated in 18–45 year old volunteers, with the highest dose also evaluated in an older age, 55–75 years, cohort. Study drug has been well tolerated in both the young and the older age cohorts, with no safety issues observed. A plateau effect in terms of FVIII level inhibition has been observed. At plateau, FVIII levels were generally decreased by 1/3 to 2/3 from baseline. aPTT prolongation (generally 1.1–1.2 times baseline) was also observed whereas the Prothrombin time (PT) was not modified. aPTT prolongations at doses of ≥ 620 μg/kg were generally maintained for at least 4 weeks. Long half-life of drug and associated anticoagulant effect are supported by the finding of consistent and prolonged effect on aPTT. In conclusion, this study demonstrates that in healthy young and older volunteers a single administration of TB-402 results in a prolonged anticoagulation effect without the risk of overdosing or spontaneous hemorrhage. TB-402 will next be evaluated in patients at risk for venous thromboembolism.

scholarly journals 631. Preliminary safety and pharmacokinetic profile of VIR-2482: a monoclonal antibody for the prevention of influenza A illness

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S376-S376
Author(s):  
Jennifer Sager ◽  
David K Hong ◽  
Aurelio Bonavia ◽  
Lynn Connolly ◽  
Deborah Cebrik ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Single Dose ◽  
Half Life ◽  
Influenza A ◽  
Phase 1 ◽  
Safety Data ◽  
Phase 2 ◽  
Independent Contractor ◽  
Post Dose ◽  
Phase 2 Study

Abstract Background VIR-2482 is a fully human immunoglobulin G1(IgG) monoclonal antibody (mAb) directed against a highly-conserved epitope in the influenza A hemagglutinin stem region and is in clinical development for the prevention of influenza A illness. The Fc region of VIR-2482 has been modified to provide an extended half-life. Methods This is a randomized, placebo-controlled, Phase 1/2 study of VIR-2482 administered intramuscularly (IM) to healthy adult volunteers aged 18-64 years old who have not received a current influenza vaccine. The Phase 1 portion of the study will evaluate the safety, tolerability, pharmacokinetic (PK), and immunogenicity profile of VIR-2482 following single (Part A) or multiple doses (Part B). The Phase 2 study will evaluate the efficacy of VIR-2482 in the prevention of influenza A illness as well as safety, tolerability, and PK. Part A is ongoing and consists of four single dose cohorts (N=25/cohort) randomized (4:1) to a single dose of VIR-2482 or placebo at 60, 300, 1200, or 1800 mg. Safety, tolerability, PK and immunogenicity will be evaluated for at least 52 weeks post-dose. Results In Part A, all 100 subjects received a single dose of VIR-2482 (N=80) or placebo (N=20). Preliminary blinded safety data for all cohorts and PK data for the 300 and 1200 mg cohorts are reported here. Dosing was well tolerated; 6% (6/100) of subjects experienced mild injection site reactions, which generally resolved within 48 hrs. Through 12 weeks post-dosing, the majority (124/126; 98.4%) of adverse events (AEs) were mild to moderate in nature, no serious AEs were reported, and no subjects discontinued due to an AE. Based on available data, exposure (Cmax and AUC) between 300 and 1200 mg of VIR-2482 increased in a dose proportional manner. The PK profile of VIR-2482 is consistent with a half-life extended IgG. Conclusion Based on available data, VIR-2482 has been well tolerated following single IM doses of up to 1800 mg in healthy subjects. The preliminary PK profile of VIR-2482 enables once per season dosing. Overall, these data support initiation of a Phase 2 study to evaluate efficacy of VIR-2482 for the prevention of influenza A illness. Disclosures Jennifer Sager, PharmD, Vir Biotechnology (Employee) David K. Hong, MD, Vir Biotechnology (Employee) Aurelio Bonavia, PhD, Vir Biotechnology (Employee) Lynn Connolly, MD, PhD, Vir Biotechnology (Employee) Deborah Cebrik, PhD, Vir Biotechnology (Independent Contractor) Marie Christine Fanget, MS, Vir Biotechnology (Employee) Erik Mogalian, PharmD, PhD, Vir Biotechnology (Employee)

scholarly journals Modeling cell infection via virus-producing cells rather than free infectious virus significantly improves fits ofin vitroviral kinetic data

2019 ◽  
Author(s):  
Veronika Bernhauerová ◽  
Veronica V. Rezelj ◽  
Laura I. Levi ◽  
Marco Vignuzzi
Keyword(s):  
Mathematical Modeling ◽  
Experimental Data ◽  
Viral Load ◽  
Viral Replication ◽  
Mathematical Models ◽  
Zika Virus ◽  
Time Course ◽  
Replication Cycle ◽  
Infected Cells

AbstractChikungunya and Zika viruses are arthropod-borne viruses that pose significant threat to public health. Experimental data show that duringin vitroinfection both viruses exhibit qualitatively distinct replication cycle kinetics. Chikungunya viral load rapidly accumulates within the first several hours post infection whereas Zika virus begins to increase at much later times. We sought to characterize these qualitatively distinctin vitrokinetics of chikungunya and Zika viruses by fitting a family of mathematical models to time course viral load datasets. We demonstrate that the standard viral kinetic model, which considers that new infections result only from free virus penetrating susceptible cells, does not fit experimental data as well as a model in which the number of virus-infected cells is the primary determinant of infection rate. We provide biologically meaningful quantifications of the main viral kinetic parameters and show that our results support cell-to-cell or localized transmission as a significant contributor to viral infection with chikungunya and Zika viruses.ImportanceMathematical modeling has become a useful tool to tease out information about virus-host interactions and thus complements experimental work in characterizing and quantifying processes within viral replication cycle. Importantly, mathematical models can fill in incomplete data sets and identify key parameters of infection, provided the appropriate model is used. Thein vitrotime course dynamics of mosquito transmitted viruses, such as chikungunya and Zika, have not been studied by mathematical modeling and thus limits our knowledge about quantitative description of the individual determinants of viral replication cycle. This study employs dynamical modeling framework to show that the rate at which cells become virus-infected is proportional to the number or virus-infected cells rather than free extracellular virus in the milieu, a widely accepted assumption in models of viral infections. Using the refined mathematical model in combination with viral load data, we provide quantification of the main drivers of chikungunya and Zikain vitrokinetics. Together, our results bring quantitative understanding of the basic components of chikungunya and Zika virus dynamics.

scholarly journals Generation of monoclonal antibodies detecting specific epitopes in locust antennae

1993 ◽  
Vol 175 (1) ◽  
pp. 45-57
Author(s):  
J. Strotmann ◽  
I. Boekhoff ◽  
S. Goggerle ◽  
H. Breer
Keyword(s):  
Molecular Weight ◽  
Monoclonal Antibody ◽  
Protein Synthesis ◽  
Monoclonal Antibodies ◽  
Embryonic Development ◽  
High Molecular Weight ◽  
Time Course ◽  
Antigen Expression

1. Following a tissue-specific screening paradigm, monoclonal antibodies have been generated that interact with distinct subpopulations of cells in locust antennae. 2. Antigens were identified as high molecular weight components. 3. Immunoreactivity was not detectable during embryonic development, but rapidly appeared within a few hours of hatching. 4. The time course of antigen expression in antennal cells could be followed in situ as well as in vitro. 5. Expression of monoclonal antibody B14/6D2-like immunoreactivity was prevented by blocking protein synthesis with cycloheximide.

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