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1.
Open Forum Infectious Diseases ; 8(SUPPL 1):S634-S635, 2021.
Article in English | EMBASE | ID: covidwho-1746329

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 additional SARS-like CoVs with pandemic potential and an extended half-life. A QSP/PBPK model was constructed using ADG20-specific physiochemical properties and published non-human primate (NHP) and human PK data for other antibodies;it was used to a priori predict and confirm NHP and human PK. Methods. An existing QSP/PBPK model was modified to include 3 distinct lung sub-compartments: upper airway, lower airway, and alveolar tissue (Figure A). Each sub-compartment (Figure B) contained an epithelial lining fluid (ELF) space (Figure B). The model was fit separately to digitized NHP and human serum PK data for 7 extended half-life antibodies to estimate the apparent neonatal Fc receptor (FcRn) binding affinity (KD,FcRn) and bioavailability by drug. Nasopharyngeal swab (upper airway) and lung (lower airway) ELF PK data from 4 additional antibodies were used to optimize a single rate constant for transcytosis in lung. Patches of positive charge was a covariate on the rate of pinocytosis of antibody entry and exit from the endosomal space (Figure B). Observed NHP (ADG20 10 mg/kg IM) and human (ADG20 300 mg IM) PK data collected over the initial 21 days post dose were compared with model forecasts from a 1000-iteration simulation. Results. The distribution of fitted NHP KD,FcRn provided accurate predictions of NHP serum PK data (Figure C). NHP ADG20 KD,FcRn was optimized to be 35.7 nM and human ADG20 KD,FcRn (9.55 nM) was derived using a mean NHP:human KD,FcRn ratio of 3.74 across antibodies. Model-based simulated human serum PK data using inter-subject variability from NHP and actual weight distribution from an ongoing Phase 1 study aligned with initial 21-day data (Figure D). Using an adult CDC weight distribution (45-150 kg), the simulated median exceeded 74 days. Conclusion. The QSP/PBPK model a priori predicted NHP and human ADG20 PK. This innovative QSP-based modeling and simulation approach enabled the evaluation of candidate dose regimens prior to the availability of PK data, supporting the rapid advancement of the ADG20 clinical program during the COVID-19 pandemic.

2.
Open Forum Infectious Diseases ; 8(SUPPL 1):S635, 2021.
Article in English | EMBASE | ID: covidwho-1746328

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.

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