Rational antibody therapy for IPF

DESCRIPTION provided by applicant Idiopathic pulmonary fibrosis IPF is a chronic fatal lung disease characterized by rapid progressive loss of pulmonary function IPF is a major health problem as it affects more than typically middle aged people in the USA Quality of life rapidly deteriorates due to dyspnea and IPF associated symptoms such as pulmonary hypertension and heart failure The year mortality rate for IPF is greater than many malignancies including bladder cancer colon cancer and multiple myeloma A major need exists for effective therapeutics IPF is characterized by increased collagen deposition fibrosis by an excessive number of myofibroblasts in the lung interstitium Inappropriate proliferation and function of fibroblasts alveolar epithelial cells and embedded mesenchymal stem cells play key roles in the pathogenesis of the disease Although the molecular mechanisms that underlie this idiopathic disease have been obscure recent progress has been made Of key importance has been the identification of Wnt signaling as necessary for fibrosis in a wide variety of fibrotic diseases including IPF This is consistent with Wnt signaling playing a key regulatory role in normal wound healing tissue repair and regeneration fibrotic disease in the lung results from aberrant repair regeneration in which alveolar type AT epithelial progenitor cells stop functioning midway through repair Attenuation of Wnt signaling decreases pulmonary fibrosis in several mouse models of IPF A unifying treatment hypothesis for fibrotic disease suggests that attenuating pathologically high levels of Wnt signaling but preserving sufficient signaling will allow repair to resume We have developed a biologically active monoclonal Ab mAb that binds to the E E domains of Wnt co receptor LRP to reduce Wnt signaling by direct competition The mAb also downregulates LRP expression through endocytosis Our anti LRP mAb likely works in part by competing with the pro fibrotic Wnts that activate canonical Wnt signaling and decreasing the ability of LRP to act as a co receptor for PDGF BB CTGF and TGF mediated signaling This mAb is expected to be biologically active in a wide range of conditions it has already been shown to exert significant biological activity in mouse models of diabetic retinopathy and choroidal neovascularization We have constructed humanized versions of this mAb that bind LRP to attenuate Wnt signaling We propose to demonstrate that a humanized anti LRP mAb will sufficiently antagonize Wnt signaling in pulmonary fibrosis to inhibit progression of fibrosis of IPF and restore the cellular and extracellular milieu to permit homeostatic repair Our anti LRP humAb is postulated to be a first in class rationally designed therapy to reduce fibrosis in IPF and may be useful in other fibrotic diseases affecting the skin liver and kidney associated with aberrant Wnt signaling PUBLIC HEALTH RELEVANCE Idiopathic pulmonary fibrosis IPF is a devastating progressive and ultimately fatal lung disease We have created a rationally targeted antibody as a potential therapeutic for IPF