Novel Anti-LPA Antibody for the Treatment od Diabetic Neuropathy

描述（由申请人提供）：糖尿病在美国构成了巨大的公共卫生挑战。大约60%至70%的糖尿病患者有轻度至重度的神经系统损伤，目前还没有有效的治疗方法。因此，对新型治疗剂存在强烈的未满足的需求。生物活性脂质溶血磷脂酸（LPA）是神经病理性疼痛的关键细胞外信号分子。Lpath已经产生了针对LPA的有效和特异性的中和单克隆抗体（mAb），并且我们已经表明，用抗LPA mAb阻断LPA的活性在鼠脊髓损伤模型中具有神经保护性和促再生性，并且在良好建立的神经性疼痛动物模型中预防神经性疼痛的发作。我们建议测试的假设，即高浓度的LPA促进糖尿病神经病变的神经损伤和抗LPA治疗，通过降低LPA的水平，减少神经变性。我们将首先使用鼠mAb证明抗LPA mAb在STZ诱导的糖尿病神经病变大鼠模型中预防退行性神经病变的疗效。我们将测量神经传导速度作为大纤维运动和感觉神经功能障碍的指标，并测量爪热退缩阈值作为小纤维功能障碍的指标。Lpath还成功地人源化了抗LPA抗体，这些抗体已经在初步的体外试验中表征了它们的生物化学性质和生物活性。为了确保人源化变体的药代动力学（PK）特征不受人源化过程的损害，我们提出将人源化抗体的PK和药效学（PD）特征与鼠亲本分子的PK和药效学（PD）特征进行比较。我们将首先建立皮下给予我们的人源化抗LPA抗体的大鼠血浆中的抗体PK特征（包括AUC、消除半衰期和Cmax值）。此后，我们将使用改良的动力学排除试验（KinExA，Sapidyne Instruments）测量PK研究期间采集的血浆样本中游离抗体和LPA占据的抗体浓度。游离LPA的估计浓度将用于开发描述血浆抗体水平与LPA阻断之间关系的PK-PD模型。成功完成拟议的SBIR第一阶段项目将是计划的后续SBIR第二阶段提案提交的基础。Lpath在治疗性抗体竞技场的融资和建立合作伙伴关系方面有着良好的记录。预计在SBIR的支持下，成功计划的IND使能研究将使Lpath能够筹集资金并建立必要的公司合作伙伴关系，以将抗LPA临床候选药物推向临床开发和最终商业化。

DESCRIPTION (provided by applicant): 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.