CD40-targeting KGYY₁₅ peptides do not efficiently block the CD40–CD40L interaction

Excerpt

To the Editor: Co-signalling interactions, which include costimulatory and coinhibitory interactions and act as immune checkpoints, are important immunomodulatory therapeutic targets. Biological products that interfere with these interactions have achieved considerable clinical success in the treatment of cancer on the one hand, and autoimmune diseases and transplant recipients on the other. Alternatives to biological products are also being explored as they have the potential to lead to safer, less immunogenic, orally bioavailable agents; however, like all other protein–protein interactions, co-signalling interactions are challenging to target by smaller molecules [1]. Among these interactions, the one between CD40 and CD40 ligand (CD40L, also known as CD154) is of particular interest as a therapeutic target for the prevention of rejection in islet cell transplant recipients, as well as the prevention, or possibly even reversal, of type 1 diabetes. As published in Diabetologia [2], Wagner and co-workers designed a set of peptides to target CD40. They claimed that one of these peptides, the 15-mer KGYY₁₅, prevented hyperglycaemia in the NOD mouse model of type 1 diabetes, representing a potentially significant advancement. Recently, Coppieters and co-workers raised doubts regarding these claims in a letter [3]. Wagner and colleagues countered this in a response highlighting the complex nature of this interaction and the lack of in cellulo data [4]. …