No abstract

The respiratory tract represents the key target for antiviral delivery in early interventions to prevent severe COVID-19. While neutralizing monoclonal antibodies (mAb) possess considerable efficacy, their current reliance on parenteral dosing necessitates very large doses and places a substantial burden on the healthcare system. In contrast, direct inhaled delivery of mAb therapeutics offers the convenience of self-dosing at home, as well as much more efficient mAb delivery to the respiratory tract. Here, building on our previous discovery of Fc-mucin interactions crosslinking viruses to mucins, we showed that regdanvimab, a potent neutralizing mAb already approved for COVID-19 in several countries around the world, can effectively trap SARS-CoV-2 virus-like-particles in fresh human airway mucus. IN-006, a reformulation of Regdanvimab, was stably nebulized across a wide range of concentrations, with no loss of activity and no formation of aggregates. Finally, nebulized delivery of IN-006 resulted in 100-fold greater mAb levels in the lungs of rats compared to serum, in marked contrast to intravenously dosed mAbs. These results not only support our current efforts to evaluate the safety and efficacy of IN-006 in clinical trials, but more broadly substantiate nebulized delivery of human antiviral mAbs as a new paradigm in treating SARS-CoV-2 and other respiratory pathologies.

The respiratory tract represents the key target for antiviral delivery in early interventions to prevent severe COVID‐19. While neutralizing monoclonal antibodies (mAb) possess considerable efficacy, their current reliance on parenteral dosing necessitates very large doses and places a substantial burden on the healthcare system. In contrast, direct inhaled delivery of mAb therapeutics offers the convenience of self‐dosing at home, as well as much more efficient mAb delivery to the respiratory tract. Here, building on our previous discovery of Fc‐mucin interactions crosslinking viruses to mucins, we showed that regdanvimab, a potent neutralizing mAb already approved for COVID‐19 in several countries, can effectively trap SARS‐CoV‐2 virus‐like particles in fresh human airway mucus. IN‐006, a reformulation of regdanvimab, was stably nebulized across a wide range of concentrations, with no loss of activity and no formation of aggregates. Finally, nebulized delivery of IN‐006 resulted in 100‐fold greater mAb levels in the lungs of rats compared to serum, in marked contrast to intravenously dosed mAbs. These results not only support our current efforts to evaluate the safety and efficacy of IN‐006 in clinical trials, but more broadly substantiate nebulized delivery of human antiviral mAbs as a new paradigm in treating SARS‐CoV‐2 and other respiratory pathologies.

For long-term space missions, it is necessary to understand how organisms respond to changes in gravity. Plant roots are positively gravitropic; the primary root grows parallel to gravity's pull even after being turned away from the direction of gravity. We examined if this gravitropic response varies depending on the time of day reorientation occurs. When plants were reoriented in relation to the gravity vector or placed in simulated microgravity, the magnitude of the root gravitropic response varied depending on the time of day the initial change in gravity occurred. The response was greatest when plants were reoriented at dusk, just before a period of rapid growth, and were minimal just before dawn as the plants entered a period of reduced root growth. We found that this variation in the magnitude of the gravitropic response persisted in constant light (CL) suggesting the variation is circadian-regulated. Gravitropic responses were disrupted in plants with disrupted circadian clocks, including plants overexpressing Circadian-clock Associated 1 (CCA1) and elf3-2, in the reorientation assay and on a 2D clinostat. These findings indicate that circadian-regulated pathways modulate the gravitropic responses, thus, highlighting the importance of considering and recording the time of day gravitropic experiments are performed.