Fc receptor-mediated delivery of therapeutics in airway inflammation

Univ Of Maryland, College Park, College Park MD

Investigators

Abstract

Asthma is a chronic condition that affects approximately 300 million people worldwide, and its prevalence is on the rise. People with asthma are more susceptible to infections. The condition is characterized by increased sensitivity of the airways and occasional blockage due to an underlying uncontrolled inflammatory response. Current treatments focus on opening the airways or using anti-inflammatory drugs like corticosteroids, but these treatments are not curative and may have undesired side effects. Moreover, around 10-15% of patients, especially those with severe asthma, may develop resistance to steroids. This poses a significant challenge for healthcare systems and budgets. Therefore, there is a pressing need for a more effective intervention strategy. We and others have recently found that human and murine airway epithelial cells (AECs) express IgE Fc receptor CD23 or IgG Fc receptor FcRn. CD23 or FcRn is functionally capable of transporting IgE or IgG antibodies across the polarized epithelial cells lining the airway in humans and mice. Since AECs are the first cell layer to come into contact with inhaled proteins with therapeutic potential, these discoveries lead us to hypothesize that CD23 and FcRn can deliver an immune therapeutic protein if fused to an IgE Fc or IgG Fc fragment, across the airway barrier to gain access to underlying immune effector cells, consequently modulate or dampen the allergic inflammations and hypersensitivity responses in the airway. In our preliminary proof-of-concept studies, we used a model protein cytotoxic T-lymphocyte antigen 4 (CTLA-4) which functions as an immune checkpoint for dampening T cell activation. The intranasal (i.n.) delivery of CTLA4-Fc (CD23-mediated) or CTLA4-Fc (FcRn-mediated) fusion proteins effectively attenuated the allergic inflammations in an ovalbumin (OVA)-based murine asthma model. Hence, CD23 or FcRn-dependent transfer of Fc or Fc-fused therapeutic proteins into the airway may be useful for future interventions for alleviating allergic airway inflammation. To show these pathways in the airway represent a platform technology for delivering of therapeutic proteins, we will test our concept by using house dust mite (HDM)-based moderate or severe asthma mouse models. The moderate model is steroid-sensitive and Th2/eosinophil-driven, whereas the severe model reflects steroid-insensitive, Th1/neutrophil-predominant asthma phenotypes. We will test the therapeutic effects of Fc fusion proteins to directly cure asthma by modifying the underlying immune responses in these asthma models. This strategy will ensure the reproducibility of results and the success of this study.