Barriers for orally inhaled therapeutic antibodies

ABSTRACTIntroduction Respiratory diseases represent a worldwide health issue. The recent Sars-CoV-2 pandemic, the burden of lung cancer, and inflammatory respiratory diseases urged the development of innovative therapeutic solutions. In this context, therapeutic antibodies (Abs) offer a tremendous opportunity to benefit patients with respiratory diseases. Delivering Ab through the airways has been demonstrated to be relevant to improve their therapeutic index. However, few inhaled Abs are on the market.Areas covered This review describes the different barriers that may alter the fate of inhaled therapeutic Abs in the lungs at steady state. It addresses both physical and biological barriers and discusses the importance of taking into consideration the pathological changes occurring during respiratory disease, which may reinforce these barriers.Expert opinion The pulmonary route remains rare for delivering therapeutic Abs, with few approved inhaled molecules, despite promising evidence. Efforts must focus on the intertwined barriers associated with lung diseases to develop appropriate Ab-formulation-device combo, ensuring optimal Ab deposition in the respiratory tract. Finally, randomized controlled clinical trials should be carried out to establish inhaled Ab therapy as prominent against respiratory diseases.KEYWORDS: Biological barriersinhalationlungsmucustherapeutic antibodyPK/PD Article highlights Inhaled Ab therapy has been shown to be success in the treatment of respiratory disease in several preclinical models and early clinical trials.Stresses associated with formulation and aerosolization processes may impair inhaled Ab activity.The lungs itself comprise several biological barriers hindering Ab deposition and efficacy.Some lung diseases (CF etc.) are associated with biological barrier changes that should be considered for the use of inhaled Ab.It is important to integrate the challenges of Ab inhalation early during drug development for program success.AcknowledgmentsThe figures were created with Biorender.comDeclaration of interestN Heuze-Vourc'h was co-founder and scientific expert for Cynbiose Respiratory. In the past 3 years, she received personal consultancy/expertise fees from the European agency/commission, Novartis, Immune Biosolutions, the National Research Agency (ANR), and Aleva/Telis Bioscience. The laboratory receives research support from Sanofi, CSL Behring, and Oxyvie and receipt of equipment from Aerogen Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Additional informationFundingThe work associated with this review was supported by grants provided by the French National Research Agency (ANR) as part of the "Investissements d'Avenir" program (LabEx MAbImprove, ANR-10-LABX-53-01), Region Centre-Val-de-Loire (Novantinh Program), Vaincre-la-Mucoviscodose (RF20210502871) and the European Defence Fund (CounterAct program).