Stable nebulization and muco-trapping properties of Regdanvimab/IN-006 supports its development as a potent, dose-saving inhaled therapy for COVID-19

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.

Monoclonal antibody therapies against SARS-CoV-2

“… 157 , 158 , 159 , 160 In particular, IN-006 is a muco-trapping formulation of regdanvimab that, when delivered via vibrating mesh nebuliser instead of being dosed intravenously, has resulted in 100 times higher mAb concentration levels in the lungs of rats than in serum. 161 Several investigators have proposed edible 162 or intranasal 163 egg-derived IgY for passive immunotherapy, and expression of viral antigens in the leaves of edible plants (eg, lettuce) is also being investigated to induce immunity. 164 Similarly, an inhalable, bispecific, single-domain antibody has been shown to neutralise omicron in a mouse model.…”

A randomized, double-blind, Phase 1 study of IN-006, an inhaled antibody treatment for COVID-19

“…In contrast, nebulized delivery using a handheld nebulizer enables the convenience of at-home dosing and takes only minutes to complete. Furthermore, IV, IM, and SC routes provide mAb Cmax to the airway lining fluid from the blood only after a delay of one or more days, and, even then, only achieve airway concentrations that are a fraction of the concentrations in plasma [10, 11, 14]. For instance, in a recent clinical trial of the anti-influenza mAb CR6261 given as a single 50 mg/kg dose IV, the peak nasal concentration was not achieved until 2 days after IV infusion [12] and the peak nasal concentration of 0.597 µg/mL was ∼10-fold lower than the concentrations we observed for IN-006 at the trough of our daily inhaled dosing (∼5.8 µg/mL), despite the much lower total dose of IN-006 compared to CR6261 (90 mg IN-006 vs. ∼2,000-4,000 mg CR6261 [12]).…”

“…While IN-006 levels in the LRT were not directly measured in this study, the appreciable serum concentrations and the delayed serum Tmax both strongly suggest we are efficiently delivering IN-006 into the LRT and the deep lung. Indeed, in a toxicokinetic multiple dose nebulization study of IN-006 in rats, IN-006 concentrations in airway fluid exceeded the serum concentrations by ~100-fold [14]. Efficient delivery into the LRT is a direct consequence of our design requirement for the vibrating mesh nebulizer.…”

“…Nebulization has been used to conveniently deliver protein therapeutics (e.g., Pulmozyme) directly to the lungs. Importantly, direct inhaled delivery can achieve far higher concentrations of drugs in the lungs than can be achieved by IV or IM administration, within minutes [14]. Since the pattern of deposition of nebulized drugs along the respiratory tract is largely determined by the aerosol particle size [15], it is possible to use a nebulizer that generates a broad aerosol size distribution to deliver drug throughout the entire respiratory tract, from the nasal turbinates in the URT, to conducting airways in the LRT, to the deep lung.…”

“…Regdanvimab, an IV-dosed human IgG 1 mAb directed against the SARS-COV-2 spike protein receptor binding domain (RBD), is approved in the European Union for adults with COVID-19 who do not require supplemental oxygen and who are at increased risk of progression to severe COVID-19. We previously reported the results from preclinical activities that supported a first-in-human study of inhaled IN-006 [14], including muco-trapping of SARS-CoV-2 virions, GLP nebulization stability studies, and excellent tolerability in GLP inhaled toxicology and GLP tissue cross reactivity experiments. The current report describes a Phase 1 study designed to assess the safety, tolerability, and nasal fluid and serum pharmacokinetics of nebulized IN-006 in healthy adults.…”