Charlesson, LLC — Department of Health and Human Services SBIR Phase II: W

Description

DESCRIPTION provided by applicant Diabetic retinopathy DR is a common complication of diabetes and a leading cause of vision loss in the United States Although the anti vascular endothelial growth factor VEGF drugs have shown impressive efficacies on wet age related macular degeneration AMD they are only effective in approximately of patients with DR likely due to the multi factorial nature of DR Therefore inhibition of VEGF alone may not be sufficient and alternative therapies with non VEGF targets are desired to improve the treatment of this sight threatening eye disease The Wnt pathway mediates multiple pathological processes including angiogenesis vascular permeability inflammation and fibrosis as it regulates multiple pathogenic factors such as VEGF tumor necrosis factor alpha TNF a intercellular adhesion molecule ICAM connective tissue growth factor CTGF fibronectin FN and Cox Recent research suggests that over activation of the Wnt pathway in the retina plays a key pathogenic role in the development of DR There are Wnt ligands and Fz receptors that involve in the activation of the Wnt pathway while only two cell surface co receptors low density lipoprotein receptor related protein and LRP andamp are essential for the activation of Wnt pathway Previous evidence indicates that LRP plays a major role in Wnt signaling in the retina and retinal pigment epithelia and thus LRP represents a promising molecular target for developing effective treatments of DR Through generating and screening a series of mouse anti human LRP monoclonal antibodies mAbs we have identified F mab as a specific blocker of LRP Our Phase I project showed that the anti LRP antibody specifically recognizes LRP blocks Wnt pathway reduces Wnt mediated expression of pathogenic factors including VEGF TNF a ICAM and CTGF and ameliorates multiple pathological processes of DR such as retinal vascular leakage inflammation and neovascularization Based on these observations we hypothesize that anti LRP antibody has great potential to become an effective drug for the treatment of DR since it can alleviates the major pathological processes of DR through controlling multiple pathogenic factors Due to target to a main pathway which mediates production of multiple pathogenic factors and major pathological processes of DR anti LRP antibody should be more effective for DR than the drugs with a single target Recently we have generated humanized anti LRP antibody CLT derived from its parent F mab CLT showed higher affinity to LRP and higher potency in blocking Wnt signaling than F mab Affinity of CLT is fold greater than that of the murine antibody and antibody also significantly inhibited over activation of the Wnt pathway and retinal vascular leakage The goal of this project is to complete the efficacy pharmacokinetic PK and toxicity studies of CLT required for the FDA approval of an Investigational New Drug IND application The Phase II project includes three specific aims Aim will compare efficacy of CLT and anti VEGF antibody Aim will analyze PK and ocular distribution of CLT Aim will evaluate pre GLP toxicology of CLT The proposed studies will lay a solid groundwork for future Phase III preclinical studies and IND application of CLT to develop a therapy to be used as an alternative or in combination with the anti VEGF drugs Upon the completion of the proposed studies Charlessonandapos s commercial partner Velocity Pharmaceutical Development will support and initiate Phase III preclinical studies including GMP material production and GLP toxicology study IND application and clinical trials for this drug candidate PUBLIC HEALTH RELEVANCE DR is a common complication of diabetes and a leading cause of vision loss in the United States Anti VEGF antibodies are only effective in approximately of DR patients due likely to the multi factorial nature of DR Therefore inhibition of VEGF alone may not be sufficient and there is a vital medical need to develop alternate therapies with non VEGF targets for DR This project will develop a novel and more effective approach to improve the treatment of DR