Development of PRS-220, a potential best-in-class, inhaled CTGF/CCN2 inhibitor for the treatment of IPF

Abstract

<b>Aims and objectives:</b> CTGF (CCN2), a secreted matricellular protein, has been identified as a mediator of fibrosis. First clinical validation of this target in IPF has been provided by positive results of a systemically-delivered antibody in Phase 2 clinical studies. Anticalin® proteins derived from human lipocalins can be engineered to bind to their targets with high potency and selectivity, similar to antibodies. Based on their biophysical properties, Anticalin proteins are well suited for lung delivery as demonstrated by the inhaled PRS-060/AZD1402, currently in Phase 2 studies for asthma. Here we describe the development of PRS-220, an Anticalin-based CTGF inhibitor, for treatment of IPF via inhalation. <b>Methods:</b> Phage display selection of Anticalin libraries was used for initial candidate identification and optimization. Binding characteristics of CTGF-targeting Anticalin proteins were determined using protein and cell-based assays. The PK profile and <i>in vivo</i> potency of CTGF-binding Anticalin proteins upon lung delivery were assessed in healthy and bleomycin-challenged mice. <b>Results:</b> We identified Anticalin proteins binding to different epitopes of CTGF with picomolar affinities. Target engagement was confirmed with CTGF-expressing, TGF-β1-stimulated primary human lung fibroblasts. Lung delivery of CTGF-targeting Anticalin proteins in bleomycin-challenged mice attenuated fibrotic lung remodeling <i>in vivo</i>. <b>Conclusion:</b> Here we report the identification of a novel class of high affinity CTGF inhibitors for treatment of IPF using the Anticalin technology. The preclinical and developability data support further development of PRS-220 as a potential best-in-class inhaled IPF therapy.