Thursday, November 21, 2024
11/21/2024
Rational antibody therapy for IPF ABSTRACT Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease with rapid, progressive loss of pulmonary function. Five year mortality rate (20-40%) 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. Wnt signaling appears to be 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 is hypothesized to result from aberrant repair/regeneration in which alveolar type 2 (AT2) 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 attenuating pathologically high levels of Wnt signaling, yet preserving sufficient signaling to permit repair to resume. We have developed a biologically active monoclonal Ab (mAb) that binds to the E1/E2 domains of Wnt co- receptor LRP6 to reduce Wnt signaling by direct competition. The mAb also down-regulates LRP6 expression through endocytosis, Our anti-LRP6 mAb likely works in part by competing with the pro-fibrotic Wnts that activate canonical Wnt signaling AND decreasing the ability of LRP6 to act as a co-receptor for PDGF-BB, CTGF and TGF-beta mediated signaling. This mAb demonstrates significant biological activity in mouse models of diabetic retinopathy, choroidal neovascularization and diabetic kidney disease. In phase I we constructed humanized versions of this mAb (HuLRP6) that a) bind LRP6 to attenuate Wnt signaling and b) reduced fibrosis in a mouse model of pulmonary fibrosis. In Phase II these studies will be expanded to show that HuLRP6 can 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. We will produce HuLRP6 at sufficient levels to conduct preclinical toxicology, pharmacokinetic and additional efficacy studies. HuLRP6 is expected to be a first-in-class rationally designed therapy to reduce fibrosis in IPF, capable of completely blocking progression and possibly reverting fibrosis and may be useful in other fibrotic diseases associated with aberrant Wnt signaling affecting the skin, liver, heart and kidney. Phase I: 1 R43 HL090189-01A2
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