CRYSTAL-SHINE · A nanobody imaging tool to detect protein crystals and predict therapeutic response in asthmatics

Asthma is characterized by airway obstruction, causing difficulty in breathing. The major cause of therapy resistant obstruction is mucus plug buildup in 60% of severe asthmatics. Mucus plugs form as a result of abnormal mucus production by airway barrier cells and recruitment of eosinophils that change the mucus from a gel- to a glue-like state. Eosinophils also release galectin-10 (Gal10) protein, which crystallizes and forms Charcot-Leyden crystals (CLC). My advanced ERC grant unraveled how CLCs damage the epithelium to aggravate airway inflammation, cause more mucus build-up and physically impede the clearance of plugs, because of their needle-like shape. We therefore developed crystal-dissolving antibodies, that improve mucus clearance in mice. Meanwhile we also found that chronic rhinosinusitis (CRS) and 10% of cystic fibrosis (CF) patients have CLC-rich mucus. The current problem we are facing in the further clinical development of crystal dissolving antibodies is that we do not have a biomarker for CLC-rich mucus, and therefore it would be hard to predict which patients benefit from treatment with CLC-dissolving antibodies. The solution is to develop a non-invasive imaging technique to visualize crystal-containing mucus. We have therefore generated a Gal10 PET tracer. We have developed humanized mice that express Gal10 and form CLCs in their airways, and will be used to test the feasibility of Gal10 PET tracer imaging. A major challenge is to find the best conjugation format of the PET biomarker, and unravel the pharmacokinetics and - dynamics of the imaging modality. In parallel, we will test if Gal10 antibodies bind to human biopsies from asthma, CRS and CF patients, and how this biomarker correlates to CLC presence. Gaining PoC that Gal10 PET imaging works as a biomarker to detect CLCs will personalize the approach and create deal-making value for our antibody program.