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Stable nebulization and muco-trapping properties of regdanvimab/IN-006 support 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, 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.

SUBMITTER: McSweeney MD

PROVIDER: S-EPMC9537933 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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

McSweeney Morgan D MD Stewart Ian I Richardson Zach Z Kang Hyunah H Park Yoona Y Kim Cheolmin C Tiruthani Karthik K Wolf Whitney W Schaefer Alison A Kumar Priya P Aurora Harendra H Hutchins Jeff J Cho Jong Moon JM Hickey Anthony J AJ Lee Soo Young SY Lai Samuel K SK

Bioengineering & translational medicine 20220830

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 t ...[more]

PMID: 36248234

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Project description:BackgroundCoronavirus disease 2019 (COVID-19) is an ongoing public health crisis that has led to many deaths due to multiple organ dysfunction syndromes (MODS). This article describes the clinical characteristics, management, and outcomes of critically ill COVID-19 patients who survived the disease through mechanical circulatory support (MCS).MethodsWe studied 25 critically ill COVID-19 patients who underwent MCS from January 20, 2020, to April 10, 2020, at the Tongji Hospital of Huazhong University of Science and Technology.ResultsThirteen (52%) of the 25 patients survived with MCS support, while 12 (48%) died. At the time of their hospital admission, we identified significant differences in their peak cardiac troponin I (cTnI) and interleukin 6 (IL-6) levels, as well as in their lymphocyte count and C-reactive protein (CRP) levels. Cox proportional hazards regression model revealed that receipt of renal replacement therapy (RRT) was associated with an approximately 20-fold improvement in survival [hazard ratio (HR) =0.049, 95% confidence interval (CI) =0.008 to 0.305]. The number of days spent on extracorporeal membrane oxygenation (ECMO) support and the use of hydrogen (pH) at the time of MCS was also associated with an increase in survival. This contrasted with high-sensitivity C-reactive proteins (hs-CRP) and lactate, associated with a decrease in survival during MCS. Further analysis of the determinants relating to a COVID-19 patient's chance of survival on/after MCS was also indicated by levels of IL-6 (β=0.009, P=0.006), IL-8 (β=0.031, P=0.020), and TNF-α (β=0.107, P=0.014), which saw a significant increase in the 12 patients who died. This contrasts with the non-significant decrease in IL-6, IL-8, and TNF-α levels in the 13 patients who survived.ConclusionsThese results indicate that pH, lactate, hs-CRP, ECMO duration, and RRT are important clinical determinants for assessing how MCS can increase the chances of critically ill COVID-19 patients surviving the disease.

Dataset Information

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

Publications

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

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