Development of MMP-9 inhibitory monoclonal antibodies to relieve neuropathic pain

PROJECT SUMMARY Diabetic neuropathic pain affects millions of Americans but there continues to be an unmet need for safe and effective pain medications. Opioids and nonsteroidal anti-inflammatory drugs dominate the clinical landscape despite limited effectiveness and considerable side-effect profiles. Recent advances in understanding of the pathogenesis of neuropathic pain suggest that mechanism- rather than symptom-based treatments hold the key to the development of new successful therapies. Particularly, matrix metalloproteinase (MMP)-9 has been identified to be both required and sufficient for producing neuropathic pain symptom, and thus presents as an attractive target for effective management of diabetic neuropathic pain. Apart from small molecule inhibitors usually lacking specificity, our previous work has isolated a panel of monoclonal antibody (mAb) inhibitors showing exclusive selectivity toward MMP-9. In mouse models of type 1 and type 2 diabetes, these mAb MMP- 9 inhibitors alleviated mechanical and cold pain, promoted nerve fiber regeneration, and enhanced mitochondria function. Our long-term goal is to achieve effective and safe treatment for neuropathic pain. This UG3-UH3 project aims to develop a mechanism-based non-addictive mAb therapeutic for diabetic neuropathic pain. More specifically, we will conduct preclinical optimization and translational development and advance one lead anti- MMP9 inhibitory mAb with high potency and selectivity to Phase I clinical trial for diabatic neuropathic pain. Accordingly, we propose five key objectives to accomplish in the early therapeutic development process: (1) Hit to Lead; (2) Lead Optimization and PK/PD Development; (3) Lead Characterization and Biomarker Identification; (4) IND-Enabling Studies; and (5) Phase I Clinical Trial. The proposed research is clinically significant, because it will develop an effective and safe mAb therapeutic for treating diabetic neuropathic pain symptoms and the underlying causes. The project is innovative because it will discover and engineer highly specific MMP-9 mAb inhibitors and develop a mechanism-based rather than symptom-based treatment. If successful, the MMP-9 mAb inhibitor will be the first-in-class mechanism-based non-addictive analgesic therapy for the management of diabetic neuropathic pain.