GB05, a safe and effective IFNα1b inhalation solution for treating respiratory syncytial virus infection

Abstract

Human respiratory syncytial virus (HRSV) infection is linked to significant morbidity and mortality in infants and young children worldwide, yet no effective treatment is available. Interferon α (IFNα), a major subtype among the IFN family, has demonstrated antiviral effects by activating the human immune system. Aerosol inhalation is a way of IFN administration that can enhance efficacy while decreasing serum IFNα concentrations and systemic exposure, thereby minimizing the risk of systemic toxicity. However, at present, human interferon α1b (IFNα1b) injection solution is used off-label for inhalation, raising safety concerns for infants. Additionally, natural IFNα1b contains a free sulfhydryl group from cysteine residue, increasing the risk of structural instability. Human serum albumin (HSA), an excipient in IFNα1b formulations, may pose safety risks to infants. To address these concerns, we developed GB05-human IFNα1b inhalation solution with optimized molecular design, expression system and formulation. First, GB05 protein was expressed in the periplasmic space to achieve easier purification. GB05 was engineered with a C86S mutation to prevent the formation of intermolecular disulfide bonds. Furthermore, GB05 was formulated according to regulations for inhalation solution, with a minimal HSA of 0.1 %, to ensure safety while preserving biological activity and stability. Plasma concentrations of GB05 following nebulization in cynomolgus macaques were significantly lower than those in the lungs, suggesting a reduced risk of systemic adverse events. Finally, GB05 showed good efficacy against HRSV infection in vitro and in vivo. In summary, GB05 is the first reported IFN inhalation solution manufactured in compliance with regulatory standards, to our knowledge, exhibiting safety and efficacy due to effectively local delivery. GB05 will fill the gap in the treatment of HRSV infection.