Objective

In response to infections and irritants, the respiratory epithelium releases the alarmin interleukin (IL)-33 to elicit a rapid immune response. This makes IL-33 an attractive target for drug discovery. Work performed at MedImmune (Cohen et al, Nature Communications 2015) has shown for the first time that IL-33 can form intra-chain disulphide bonds resulting in large conformational changes within the IL-33 protein that disrupt the binding of IL-33 to its receptor, ST2. These conformational changes occur rapidly in in vivo and in vitro, leading to challenges in identifying antibodies that can bind to and inhibit the action of IL-33. This presentation will describe how, through innovative use of mutant forms of IL-33 in antibody phage display selections and appropriate design of screening campaigns, a highly potent inhibitor of IL-33 was identified. This potential therapeutic antibody has many favourable characteristics such as a very high affinity for IL-33 and an epitope that results in potent inhibition in an in vivo mouse Alternaria challenge model. The story of this antibody discovery project is a testament to how a fundamental understanding of target structure and biology is key to the identification of potential therapeutic drug candidates