Research Project
9145665
? 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 50% 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-1 (ICAM-1), connective tissue growth factor (CTGF), fibronectin (FN), and Cox-2. 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 19 Wnt ligands and 10 Fz receptors that involve in the activation of the Wnt pathway, while only two cell-surface co-receptors, low-density lipoprotein receptor-related protein 5 and 6 (LRP5 & 6), are essential for the activation of Wnt pathway. Previous evidence indicates that LRP6 plays a major role in Wnt signaling in the retina and retinal pigment epithelia, and thus, LRP6 6 represents a promising molecular target for developing effective treatments of DR. Through generating and screening a series of mouse anti-human LRP6 monoclonal antibodies (mAbs), we have identified 2F1mab as a specific blocker of LRP6. Our Phase I project showed that the anti-LRP6 antibody specifically recognizes LRP6, blocks Wnt pathway, reduces Wnt-mediated expression of pathogenic factors including VEGF, TNF-a, ICAM-1 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-LRP6 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-LRP6 antibody should be more effective for DR than the drugs with a single target. Recently, we have generated humanized anti-LRP6 antibody (CLT-020) derived from its parent 2F1mab. CLT-020 showed higher affinity to LRP6 and higher potency in blocking Wnt signaling than 2F1mab. Affinity of CLT-020 is 35.1-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-020 required for the FDA approval of an Investigational New Drug (IND) application. The Phase II project includes three specific aims: Aim 1 will compare efficacy of CLT- 020 and anti-VEGF antibody; Aim 2 will analyze PK and ocular distribution of CLT-020; Aim 3 will evaluate pre- GLP toxicology of CLT-020. The proposed studies will lay a solid groundwork for future Phase III preclinical studies and IND application of CLT-020 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, Charlesson'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.
