SBIR-STTR Award

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 132,000, 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 20-40% 5 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 2 (AT2) 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 E1/E2 domains of Wnt co-receptor LRP6 to reduce Wnt signaling by direct competition. The mAb also downregulates 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-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 LRP6 to attenuate Wnt signaling. We propose to demonstrate that a humanized anti-LRP6 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-LRP6 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 Statement:


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.

Project Terms:
Affect; Affinity; Alveolar; Antibodies; Antibody Therapy; Attenuated; attenuation; base; beta catenin; Binding (Molecular Function); Biological; Bleomycin; Cell Culture Techniques; Cell Line; Cell physiology; Choroidal Neovascularization; Chronic; clinical toxicology; Collagen; Colon Carcinoma; Complex; connective tissue growth factor; Deposition; design and construction; Diabetic Retinopathy; Disease; DNA strand break; Drug Stability; Dyspnea; Endocytosis; Epithelial; Epithelial Cells; Evaluation; extracellular; Family; Fibroblasts; fibrogenesis; Fibrosis; Fluorescein; Goals; Hamman-Rich syndrome; Health; Heart failure; In Vitro; in vivo; in vivo Model; Injury; Isothiocyanates; Kidney; Lead; lipoprotein receptor-related protein 6; Liver; Lung; Lung diseases; Malignant neoplasm of urinary bladder; Malignant Neoplasms; Mediating; member; Mesenchymal; Mesenchymal Stem Cells; middle age; Modeling; Molecular; Mortality Vital Statistics; mouse model; Multiple Myeloma; Mus; Myofibroblast; Natural regeneration; Pathogenesis; Pathology; Phase; phase 2 study; platelet-derived growth factor BB; Play; pre-clinical; Preparation; Production; public health relevance; Pulmonary Fibrosis; pulmonary function; Pulmonary Hypertension; Quality of life; Radiation; receptor; repaired; Retinal; Rodent; Role; scale up; Signal Transduction; Skin; Stem cells; Symptoms; Therapeutic; therapy design; tissue regeneration; tissue repair; Toxicology; Work; Wound Healing

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

Public Health Relevance Statement:
Project Narrative 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.

Project Terms:
Affect; Alveolar; Antibodies; Antibody Therapy; Attenuated; attenuation; beta catenin; Binding; Biological; Bleomycin; Cell physiology; Choroidal Neovascularization; Chronic; Clinical Trials; Collagen; Colon Carcinoma; Complex; connective tissue growth factor; Deposition; Diabetic Nephropathy; Diabetic Retinopathy; Disease; Drug Kinetics; efficacy study; Endocytosis; Epithelial Cells; extracellular; Fibroblasts; Fibrosis; Genetic; Hamman-Rich syndrome; Heart; Human; human monoclonal antibodies; In Vitro; in vivo; Kidney; Ligands; Liver; Lung; Lung diseases; Malignant neoplasm of urinary bladder; Malignant Neoplasms; Mediating; Mediator of activation protein; Mesenchymal Stem Cells; Molecular; mortality; mouse model; Multiple Myeloma; Myofibroblast; Natural regeneration; Oklahoma; Pathogenesis; Pathologic; Phase; phase 2 study; Pirfenidone; platelet-derived growth factor BB; Platelet-Derived Growth Factor Receptor; Play; pre-clinical; Pulmonary Fibrosis; pulmonary function; receptor; repaired; Rodent; Role; Signal Transduction; Skin; standard of care; Stem cells; synergism; Testing; Therapeutic; therapy design; Time; tissue regeneration; tissue repair; Toxic effect; Toxicology; Transforming Growth Factor beta; Treatment Efficacy; Universities; WNT Signaling Pathway; Work; Wound Healing