Developing A Novel Therapy for Diabetic Retinopathy

DESCRIPTION (provided by applicant): Diabetic retinopathy (DR) is a common complication of diabetes and a leading cause of vision loss in the United States. Unfortunately, there is no FDA-approved pharmacotherapy for DR. Current treatments in clinical practice and trails, such as laser photocoagulation, corticosteroids and anti-vascular endothelial growth factor (VEGF) agents, are effective in some, but not in all, DR patients. Therefore, there is an urgent medical need to develop alternate approaches for treating this sight-threatening disease. The Wnt pathway mediates multiple pathological processes, including angiogenesis, vascular permeability, inflammation and fibrosis, as it regulates many pathogenic factors, such as VEGF, tumor necrosis factor-alpha(TNF- ), intercellular adhesion molecule-1 (ICAM-1), connective tissue growth factor (CTGF), fibronectin (FN), and Cox-2. Recent research suggests the Wnt pathway plays a pathogenic role in the development of DR. There are 19 Wnt ligands and 10 Fz receptors that involves in the activation of the Wnt pathway, while only two cell surface co-receptors, low-density lipoprotein receptor-related protein 5 and 6 (LRP5 and 6), are essential for the activation of Wnt pathway. Thus, LRP5/6 becomes an attractive target for developing effective treatments of DR. Through generating and screening a series of mouse anti-human LRP6 monoclonal antibodies (mAbs), 2F1mab has been identified as a specific anti-LRP6 mAb and a potent Wnt inhibitor. Preliminary data showed that 2F1mab specifically recognizes LRP6, blocks Wnt pathway, reduces Wnt-mediated multiple pathogenic factors including VEGF, TNF- , ICAM-1 and CTGF, and inhibits multiple pathological processes of DR such as retinal vascular leakage, inflammation and neovascularization. Based on these observations, we hypothesize that 2F1mab 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. Thetherapeutic potential of 2F1mab strongly warrants further development of an antibody-based therapy modality which is suitable to clinical use in DR patients. The goal of this project is to generate a humanized therapeutic antibody derived from its parent 2F1mab for the treatment of DR. We have produced a series of humanized antibodies. Among them, the clone CLT-020 binds to LRP6 with a high specificity and affinity. Its affinity is 35.1-fold greater than 2F1mab, suggesting that CLT-020 is more effective than 2F1mab. This SBIR Phase I project will serve as a proof-of-concept study to produce CLT-020 and determine its in vivo efficacy. The program includes two specific aims: Aim 1 will establish a stable cell line to produce large amounts of CLT-020. Aim 2 will evaluate the efficacies of CLT-020 on the Wnt pathway, retinal vascular leakage and inflammation in a diabetic animal model. The proposed studies will lay a solid groundwork for future Phase II preclinical studies of CLT-020 and this project may develop a more effective therapeutics to cure DR. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Diabetic retinopathy is a common complication of diabetes and a leading cause of vision loss in the United States. There is no FDA-approved pharmacotherapy for diabetic retinopathy and current medications for diabetic retinopathy are unsatisfactory. Therefore, there is a vital medical need to develop alternate therapies for diabetic retinopathy. This project will develop a novel and more effective approach to improve the treatment of this sight-threatening disease.