Gallardo Toledo, E. | bioRxiv Science

bioRxiv2026

The biodistribution and effect of post-exposure neutralising monoclonal antibody treatment in a mouse model of SARS-CoV-2 infection with viral spread to the brain

Ronapreve, a combination of two neutralising monoclonal antibodies, casirivimab and imdevimab, was amongst the authorised treatments against SARS-CoV-2 early in the COVID-19 pandemic. Ronapreve has lost some of its efficiency with the rise of new virus variants, however, it remains a valuable tool for experimental studies to gain insights into the mechanisms and effects of anti-viral drugs. In this study we combined morphological, pharmacokinetic and molecular approaches (including multiomics) to investigate the biodistribution of Ronapreve in the K18-hACE2 murine model of SARS-CoV-2 neuroinvasion, as well as possible consequences for the brain. We also investigated the effect of the treatment on the infection status. Our results showed that after intraperitoneal injection, Ronapreve accumulates in the serum and is unable to cross the blood-brain barrier, thus not reaching the brain parenchyma; treatment has only a minimal effect on the brain transcriptome, with no significant changes in the brain lipidome or metabolome. Nonetheless, post-exposure Ronapreve treatment resulted in reduced viral loads in the lung and, in particular, the brain, with markedly reduced tissue response in the brain, as shown by the transcriptomic analysis. The results suggest a peripheral mode of action of Ronapreve to block brain infection, possibly by lowering viral replication in the nasal epithelium, reducing a subsequent spread to the brain.

pathology↗

bioRxiv2025

Investigation of anti-SARS CoV-2 multimeric bicyclic peptide inhibitors in a range of pre-clinical therapeutic settings

The spread of respiratory viruses, such as Influenza and SARS-CoV-2 has presented significant challenges over the last 30 years with few effective therapeutic options available to this day. Bi-cyclic peptides represent a unique, modular, modality in the antiviral armamentarium against future pandemics. This study provides a deeper evaluation of multivalent bi-cyclic (Bicycle(R)) molecule efficacy in several preclinical SARS-CoV-2 challenge settings. We explore both pre-exposure prophylaxis and post-exposure therapeutic settings via subcutaneous and intranasal routes of administration. We contextualize this further in bespoke scenarios of immune compromisation, and viral transmission. Promisingly, in all studies we observe efficacy, significantly reducing infectious viral burden at each study endpoint. These data further support candidacy of Bicycle molecules as a differentiated antiviral therapeutic class in the context of pandemic preparedness. ImportanceThe COVID-19 pandemic, triggered a rapid wave of innovation, accelerating the delivery of new vaccine technology and anti-viral treatments. In our first paper, we described the discovery and molecular optimization of Bicycle molecules as a novel drug class for the potential treatment of SARS CoV-2. Here, we have performed deeper characterization of these molecules in established animal models that simulate SARS-CoV-2 transmission, testing more convenient delivery routes, such as intra-nasal. The Bicycle molecules demonstrated positive outcomes in each of these studies and suggest that Bicycle molecules, as convenient and effective anti-viral treatments, could be an important addition to help future preparedness against new viral pandemics.

pharmacology and toxicology↗