A First-in-Human Randomized Study to Assess the Safety, Tolerability, Pharmacokinetics, and Neutralization Profile of Two Investigational Long-Acting Anti-SARS-CoV-2 Monoclonal Antibodies.

INTRODUCTION: COVID-19 remains a significant risk for the immunocompromised given their lower responsiveness to vaccination or infection. Therefore, passive immunity through long-acting monoclonal antibodies (mAbs) offers a needed approach for pre-exposure prophylaxis (PrEP). Our study evaluated safety, anti-SARS-CoV-2 neutralizing activity, nasal penetration, and pharmacokinetics (PK) of two half-life-extended investigational mAbs, AER001 and AER002, providing the first demonstration of upper airway penetration of mAbs with the LS-modification. METHODS: This randomized, double-blind, placebo-controlled phase I study enrolled healthy adults (n = 80) who received two long-acting COVID mAbs (AER001 and AER002), AER002 alone, or placebo. The dose ranged from 100 mg (mg) to 1200 mg per mAb component. The primary objective was to describe the safety and tolerability following intravenous (IV) administration. Secondary objectives were to describe PK, anti-drug antibodies (ADA), neutralization activity levels, and safety evaluation through 6 months of follow-up. RESULTS: The majority (97.6%) of the reported adverse events (AE) post administration were of grade 1 severity. There were no serious adverse events (SAE) or ADAs. AER001 and AER002 successfully achieved an extended half-life of 105 days and 97.5 days, respectively. Participants receiving AER001 and AER002 (300 mg each) or AER002 (300 mg) alone showed 15- and 26-fold higher neutralization levels against D614G and omicron BA.1 than the placebo group 24 h post-administration. Single 300 or 1200 mg IV dose of AER001 and AER002 resulted in nasal mucosa transudation of approximately 2.5% and 2.7%, respectively. CONCLUSION: AER001 and AER002 showed an acceptable safety profile and extended half-life. High serum neutralization activity was observed against D614G and Omicron BA.1 compared to the placebo group. These data support that LS-modified mAbs can achieve durability, safety, potency, and upper airway tissue penetration and will guide the development of the next generation of mAbs for COVID-19 prevention and treatment. TRIAL REGISTRATION: EudraCT Number 2022-001709-35 (COV-2022-001).

Description and evaluation of a delivery system for aerosolized prostacyclin.

INTRODUCTION: Inhaled vasodilators such as nitric oxide and aerosolized prostacyclin (PGI(2)) are used to treat severe hypoxemia in acute respiratory distress syndrome. Preferential distribution of nitric oxide and PGI(2) to ventilated areas of the lung causes selective pulmonary vasodilation, improved ventilation/perfusion matching, and decreased hypoxemia. Because of the technical limitations of previously described methods, we developed a PGI(2) delivery technique that allows the aerosolized drug dose to be easily calculated, set, and adjusted. METHODS: A 50 mL solution of PGI(2) (3.0x10(4) ng/mL) and a 500 mL normal saline solution were infused by a dual-channel volumetric infusion pump into a MiniHEART jet nebulizer that has a manufacturer-specified output of 8 mL/h at a set flow of 2 L/min. By adjusting the pump infusion rate to achieve a total output of 8 mL/h, the PGI(2) concentration was altered to deliver a calculated aerosolized dose of 10-50 ng/kg/min. The effectiveness of the delivery system was retrospectively evaluated by way of the responses of 11 severely hypoxemic acute respiratory distress syndrome patients who received PGI(2) via the system we describe. The MiniHEART nebulizer output, particle size, and dose delivery were evaluated in a laboratory bench study, using a set flow of 2 L/min. RESULTS: Aerosolized PGI(2) therapy (mean dose 28 +/- 17 ng/kg/min, range 10-50 ng/kg/min) significantly increased the ratio of P(aO)(2) to fraction of inspired oxygen (P(aO)(2)/F(IO)(2)) (60 +/- 11 mm Hg vs 80 +/- 17 mm Hg, p = 0.003) and arterial oxygen saturation measured via pulse oximetry (86 +/- 8% vs 94 +/- 3%, p = 0.005) (differences evaluated with the Wilcoxon signed rank test). There was no difference in positive end-expiratory pressure, mean airway pressure, or F(IO)(2), before and after aerosolized PGI(2) (p > 0.05). Nebulizer output was 6.8 +/- 0.9 mL/h, range 6.0-7.8 mL/h. The inhaled aerosol particles had a mass median diameter of 3.1 micro m. Emitted dose was 67 +/- 13% (range 57-81%) of the calculated dose. CONCLUSION: Our system is effective in delivering aerosolized PGI(2) to the alveolar-capillary interface, as indicated by significant oxygenation improvements soon after therapy commenced. The performance of the MiniHEART nebulizer varies from the manufacturer's specifications, which may alter the delivered dose.

The Th2 lymphocyte products IL-4 and IL-13 rapidly induce airway hyperresponsiveness through direct effects on resident airway cells.

Airway inflammation and airway hyperresponsiveness (AHR) are hallmarks of asthma. Cytokines produced by T helper type 2 (Th2) lymphocytes have been implicated in both processes. There is strong support for the idea that Th2 cytokines can produce AHR indirectly by promoting the recruitment of inflammatory cells. Less attention has been given to the possibility that Th2 cytokines might induce AHR by acting directly on resident airway cells. To investigate this, we polarized and activated CD4(+) T cells in vitro and analyzed airway function after administration of lymphocyte-conditioned media to the airways of naive mice. Th2-lymphocyte-conditioned medium induced AHR within 6 h. This finding was reproduced in mast-cell-deficient and in T- and B-lymphocyte-deficient mice. AHR did not occur when Th2-lymphocyte-conditioned medium was administered to mice lacking the IL-4 receptor alpha subunit or Stat6, suggesting a critical role for interleukin (IL)-4 and/or IL-13. This was confirmed by the finding that recombinant IL-4 and IL-13 both induced AHR within 6 h. The induction of AHR occurred in the absence of inflammatory cell recruitment or mucus production. These results strongly suggest that products of activated Th2 lymphocytes can rapidly perturb airway function through direct effects on resident airway cells.