Pharmacokinetic assessment of two IgG1 kappa monoclonal antibodies neutralising the SARS-CoV-2: A study in Syrian hamsters and ICR CD1 outbred mice

INTRODUCTION. Еvaluation of pharmacokinetics of monoclonal antibodies (mAb) products requires careful selection of the relevant animal models to ensure translational relevance of the data. To solve this problem, the pharmacokinetic parameters of two human monoclonal antibodies neutralising SARS-CoV-2 were evaluated in two types of laboratory animals — Syrian hamsters and mice.

AIM. This study aimed to evaluate the pharmacokinetic parameters of two different human IgG1 kappa antibodies (mAb iC1 and mAb iB20) neutralising SARS-CoV-2 after a single intravenous administration to Syrian hamsters and ICR CD1 outbred mice.

MATERIALS AND METHODS. A pilot study was performed on 15 male Syrian hamsters who received a single 5 mg/kg intravenous dose of mAb iC1. Blood samples were collected prior to administration and at 10 time points for 144 hours. In the main study, ICR CD1 mice (4 groups of 60 animals) received single intravenous doses of mAb iC1 and mAb iB20 at doses of 5 and 50 mg/kg. Blood samples were collected prior to administration and at 11 time points for 504 hours. Serum antibody concentrations were determined by enzyme-linked immunosorbent assay (ELISA). The ELISA assay was validated by following parameters: selectivity, lower limit of quantitation, calibration range, accuracy, precision, and analyte stability. Pharmacokinetic parameters — mean maximum concentration (C_max), area under the curve (AUC_0–t), mean residence time (MRT), half-life (T_1/2), and clearance (Cl) — were calculated using model-independent method of statistical moments.

RESULTS. The ELISA assays for mAb iC1 and mAb iB20 in animal blood serum were validated in the analytical range of 1.25–25.0 μg/mL and 1.25–20.0 μg/mL, respectively. C_max, AUC_0–t, and AUC_0–∞ increased significantly with the dose for both antibodies. After administration of 5 and 50 mg/kg mAb iC1 to mice the mean C_max values were about 235 and 1228 μg/mL, AUC_0–t — 6458 and 71,193 h×μg/mL. For mAb iB20 C_max values were about 359 and 4442 μg/kg, AUC_0–t — 6344 and 76,251 h×μg/mL, respectively. MRT and T_1/2 values did not depend on the administered dose. Combined with low clearance values, this indicates long-term presence of analytes in the bloodstream.

CONCLUSIONS. Pharmacokinetic parameters of mAb iC1 and mAb iB20 were determined after single administration to Syrian hamsters and ICR CD1 mice. Key parameters (C_max, AUC_0–t) were found to be dose-dependent. The obtained results can be used for further preclinical and clinical development of the medicinal products.

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