Diabetes constitutes an enormous public health challenge in USA. About 60 to 70% of people with the disease have mild to severe forms of nervous system damage and there is no effective treatment for diabetic neuropathy. Thus there is a strong unmet need for novel therapeutic agents. The bioactive lipid lysophosphatidic acid (LPA) is a key extracellular signaling molecule in neuropathic pain. Lpath has generated potent and specific neutralizing monoclonal antibodies (mAbs) against LPA and we have shown that blocking the activity of LPA with anti-LPA mAbs is neuroprotective and proregenerative in a murine spinal cord injury model and prevents the onset of neuropathic pain in well-established animal models of neuropathic pain. We propose to test the hypothesis that high concentrations of LPA promote nerve damage in diabetic neuropathy and that anti-LPA therapy, by decreasing the levels of LPA, reduces neurodegeneration. We will initially use the murine mAb to demonstrate efficacy of anti-LPA mAb in preventing degenerative neuropathy in the STZ-induced rat model of diabetic neuropathy. We will measure nerve conduction velocities as an indicator of large fiber motor and sensory nerve dysfunction, and paw thermal withdrawal thresholds as an indicator of small fiber dysfunction. Lpath has also successfully humanized anti-LPA antibodies that have been characterized for their biochemical properties and biological activities in preliminary in vitro assays. To assure that the pharmacokinetic (PK) profile of the humanized variants has not been compromised by the humanization process, we propose to compare the PK and pharmacodynamic (PD) profiles of humanized antibodies with that of the murine parental molecule. We will first establish the antibody PK profile (including AUC, elimination half-life and Cmax values) in plasma of rats dosed subcutaneously with our humanized anti-LPA antibodies. Following this, we will use a modification of the Kinetic Exclusion Assay (KinExA, Sapidyne Instruments) to measure both the concentration of free antibody and antibody occupied by LPA in plasma samples collected during the PK study. The estimated concentration of free LPA will be used to develop a PK-PD model that describes the relationship between plasma antibody levels and blockade of LPA. The successful completion of the proposed SBIR Phase I project will be the basis for a planned subsequent SBIR phase II proposal submission. Lpath has a proven track record of raising capital and establishing partnerships in the therapeutic antibody arena. It is anticipated that, with SBIR support, successful planned IND enabling studies will enable Lpath to raise capital and establish a corporate partnership necessary to move the anti- LPA clinical candidate into clinical development and eventual commercialization.
Public Health Relevance Statement: Public Health Relevance: Diabetes constitutes an enormous public health challenge in the United States. About 60 to 70% of people with the disease have mild to severe forms of nervous system damage or neuropathy and there is currently no effective treatment. Diabetic patients would benefit from research directed toward the development of new therapies that would slow, prevent, or better yet reverse nerve damage. Lpath has generated potent and specific neutralizing monoclonal antibodies that have the potential to be used therapeutically to diminish nerve dysfunction and proposes to test these antibodies to determine whether they are able to slow the progression of nerve damage in an animal model of diabetes.
NIH Spending Category: Biotechnology; Diabetes; Immunization; Neurodegenerative; Neuropathy; Neurosciences; Pain Conditions - Chronic; Pain Research
Project Terms: afferent nerve; Age related macular degeneration; analog; Animal Model; Antibodies; Antibody Therapy; base; Behavioral; Biochemical; Biological; Biological Assay; Bolus Infusion; Capital; Categories; cell type; Clinical; commercialization; Complex; Data; Development; Diabetes Mellitus; diabetic; Diabetic Neuropathies; diabetic patient; Disease; Disease Progression; Dose; drug development; Drug Kinetics; effective therapy; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Exclusion; extracellular; Fiber; Financial Support; Functional disorder; Goals; Grant; Half-Life; human disease; humanized antibody; humanized monoclonal antibodies; improved; in vitro Assay; Injection of therapeutic agent; instrument; Insulin-Dependent Diabetes Mellitus; Kinetics; Ligands; Light; Lipid Binding; Lipids; lysophosphatidic acid; Lysophosphatidic Acid Receptors; Lysophospholipids; Measures; Metabolic Pathway; Modeling; Modification; Monoclonal Antibodies; Motor; Mus; Nerve; Nerve Degeneration; nerve injury; Nervous System Trauma; Neural Conduction; Neuropathy; neutralizing antibody; neutralizing monoclonal antibodies; novel; novel therapeutics; oncology; Outcome; pain behavior; painful neuropathy; Pathway interactions; Pattern; pharmacodynamic model; Pharmacodynamics; Phase; Phase I Clinical Trials; Phospholipase A2; Plasma; Play; pre-clinical; Preclinical Testing; prevent; Process; programs; Property; public health medicine (field); public health relevance; Rattus; receptor; receptor expression; regenerative; Research; Role; Route; Sampling; sciatic nerve; Secondary to; Signal Pathway; Signal Transduction; Signaling Molecule; Small Business Innovation Research Grant; sphingosine 1-phosphate; Spinal cord injury; Streptozocin; subcutaneous; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic antibodies; Therapeutic Intervention; United States; United States National Institutes of Health; Variant; Withdrawal
