1. Ronapreve (REGN-CoV; casirivimab and imdevimab) reduces the viral burden and alters the pulmonary response to the SARS-CoV-2 Delta variant (B.1.617.2) in K18-hACE2 mice using an experimental design reflective of a treatment use case.
- Author
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Tatham L, Kipar A, Sharp J, Kijak E, Herriott J, Neary M, Box H, Gallardo Toledo E, Valentijn A, Cox H, Pertinez H, Curley P, Arshad U, Rajoli RKR, Rannard S, Stewart JP, and Owen A
- Subjects
- Animals, Mice, Humans, Disease Models, Animal, Antibodies, Viral immunology, Antibodies, Viral blood, Antibodies, Monoclonal therapeutic use, Viral Load drug effects, Angiotensin-Converting Enzyme 2 metabolism, Angiotensin-Converting Enzyme 2 genetics, Virus Replication drug effects, Female, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Monoclonal, Humanized pharmacology, Antiviral Agents pharmacology, Antiviral Agents therapeutic use, SARS-CoV-2 drug effects, SARS-CoV-2 genetics, SARS-CoV-2 immunology, SARS-CoV-2 physiology, COVID-19 virology, COVID-19 immunology, Lung virology, Lung pathology, COVID-19 Drug Treatment, Antibodies, Neutralizing immunology, Antibodies, Neutralizing blood
- Abstract
With some exceptions, global policymakers have recommended against the use of existing monoclonal antibodies in COVID-19 due to loss of neutralization of newer variants. The purpose of this study was to investigate the impact of Ronapreve on compartmental viral replication using paradigms for susceptible and insusceptible variants. Virological efficacy and impact on pathogenicity was assessed in K18-hACE2 mice inoculated with either the Delta or BA.1 Omicron variants. Ronapreve reduced sub-genomic viral RNA levels in lung and nasal turbinate, 4 and 6 days post-infection, for the Delta variant but not the Omicron variant. It also blocked brain infection, which is seen with high frequency in K18-hACE2 mice after Delta variant infection. At day 6, the inflammatory response to lung infection with the Delta variant was altered to a multifocal granulomatous inflammation in which the virus appeared to be confined. The current study provides evidence of an altered tissue response to SARS-CoV-2 after treatment with a monoclonal antibody combination that retains neutralization activity. These data demonstrate that experimental designs that reflect treatment use cases are achievable in animal models for monoclonal antibodies. Extreme caution should be taken when interpreting prophylactic experimental designs that may not be representative of treatment.IMPORTANCEFollowing the emergence of the SARS-CoV-2 Omicron variant, the WHO recommended against the use of Ronapreve in its COVID-19 treatment guidelines due to a lack of efficacy based on current pharmacokinetic-pharmacodynamic understanding. However, the continued use of Ronapreve, specifically in vulnerable patients, was advocated by some based on in vitro neutralization data. Here, the virological efficacy of Ronapreve was demonstrated in both the lung and brain compartments using Delta as a paradigm for a susceptible variant. Conversely, a lack of virological efficacy was demonstrated for the Omicron variant. Comparable concentrations of both monoclonal antibodies were observed in the plasma of Delta- and Omicron-infected mice. This study made use of a reliable murine model for SARS-CoV-2 infection, an experimental design reflective of treatment, and demonstrated the utility of this approach when assessing the effectiveness of monoclonal antibodies., Competing Interests: A.O. and S.R. are directors of Tandem Nano Ltd. and co-inventors of patents relating to drug delivery. A.O. has been a co-investigator on funding received by the University of Liverpool from ViiV Healthcare and Gilead Sciences unrelated to COVID-19 in the past 3 years. A.O. has received personal fees from Gilead and Assembly Biosciences in the past 3 years unrelated to COVID-19. A.O. was a member of the Trial Management Group for the AGILE phase I/II platform trial until January 2023 and AGILE received funding from Ridgeback and GSK in the past 3 years for which A.O. was not a co-investigator. S.R. has received research funding from ViiV and AstraZeneca, and consultancy from Gilead not related to the current paper. No other conflicts are declared by the authors.
- Published
- 2024
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