Dual Inhibition of Interleukins by Dupilumab in Asthma

Raffi Tachdjian, MD, MPH, FAAAAI, FACAAI: I don’t know if you all share the same sentiment or experience, but a lot of my colleagues in different specialties look at ours in allergy and immunology and are envious of the progress we’ve made in the last 20 years, since 2003. One of the treatments discussed was dupilumab, which is the only FDA-approved dual-interleukin inhibitor for severe asthma. Dr Chase, what does that importance look like to you between a single inhibitor vs a dual inhibitor of interleukins and eosinophilic asthma?

Nicole Chase, MD, FAAP, FACAAI, FAAAAI: Human TSLP was described in 2001, so we’ve come a long way. With the idea of single vs dual inhibitor…we think of omalizumab, mepolizumab, reslizumab, pembrolizumab, and even tezepelumab as being single-target focused. With dupilumab, by blocking a single receptor subunit, the presence of that subunit in the type 1 and type 2 receptor—which are specific to IL-4 and IL-13, respectively—is hitting 2 of 3 canonical cytokines of type 2 inflammation, so IL-4 and IL-13. As a result, IL-4 is traditionally thought of as relating to immune pathways, immune cells, and whatnot. IL-4 is very important for class switching from IgG to IgE, which is the standard process in all forms when a patient is atopic.

IL-4 and IL-13 both are involved in eosinophil trafficking. There’s not as much of that growing up of eosinophils and maintenance of them, but more leading them to where they need to go to affect their functions, which are to cause inflammation and eradicate whatever is going on, in this case inappropriately in the lungs. Finally, IL-13 in that second receptor subtype, of which the IL-4 alpha subunit is part, is present mostly in structural cells. We’re thinking about the actual epithelium of the lungs and the cells that are affected and that have that receptor, some of which will be goblet cells.

Dr Dareen Siri talked about mucus hypersecretion as being a component of asthma. We talked about the idea of smooth-muscle hypertrophy or proliferation. In that sense, you’re seeing an effect with a single drug on 2 classic cytokines and 3 of the classic biomarkers that we think about: IgE, eosinophils, and as a result, that fractional exhaled nitric oxide that we can measure in our offices. You’re getting a much broader calming down of that type 2 inflammatory response than you would see with any of the other biologics that are more single target focused.

Transcript edited for clarity