Rational antibody therapy for IPF

Rational antibody therapy for IPF ABSTRACTIdiopathic pulmonary fibrosisIPFis a chronic fatal lung disease with rapidprogressive loss of pulmonary functionFive year mortality ratefor IPF is greater than many malignanciesincluding bladder cancercolon cancer and multiple myelomaA major need exists for effective therapeuticsIPF is characterized by increased collagen depositionfibrosisby an excessive number of myofibroblasts in the lung interstitiumInappropriate proliferation and function of fibroblastsalveolar epithelial cellsand embedded mesenchymal stem cells play key roles in the pathogenesis of the diseaseWnt signaling appears to be necessary for fibrosis in a wide variety of fibrotic diseases including IPFThis is consistent with Wnt signaling playing a key regulatory role in normal wound healingtissue repair and regenerationFibrotic disease is hypothesized to result from aberrant repair regeneration in which alveolar typeATprogenitor cells stop functioning midway through repairAttenuation of Wnt signaling decreases pulmonary fibrosis in several mouse models of IPFA unifying treatment hypothesis for fibrotic disease suggests attenuating pathologically high levels of Wnt signalingyet preserving sufficient signaling to permit repair to resumeWe have developed a biologically active monoclonal AbmAbthat binds to the EEdomains of Wnt coreceptor LRPto reduce Wnt signaling by direct competitionThe mAb also down regulates LRPexpression through endocytosisOur anti LRPmAb likely works in part by competing with the pro fibrotic Wnts that activate canonical Wnt signaling AND decreasing the ability of LRPto act as a co receptor for PDGF BBCTGF and TGF beta mediated signalingThis mAb demonstrates significant biological activity in mouse models of diabetic retinopathychoroidal neovascularization and diabetic kidney diseaseIn phase I we constructed humanized versions of this mAbHuLRPthat abind LRPto attenuate Wnt signaling and breduced fibrosis in a mouse model of pulmonary fibrosisIn Phase II these studies will be expanded to show that HuLRPcan sufficiently antagonize Wnt signaling in pulmonary fibrosis to inhibit progression of fibrosis of IPF and restore the cellular and extracellular milieu to permit homeostatic repairWe will produce HuLRPat sufficient levels to conduct preclinical toxicologypharmacokinetic and additional efficacy studiesHuLRPis expected to be a first in class rationally designed therapy to reduce fibrosis in IPFcapable of completely blocking progression and possibly reverting fibrosis and may be useful in other fibrotic diseases associated with aberrant Wnt signaling affecting the skinliverheart and kidneyPhase IRHLA