Monoclonal Antibodies for Osteoporosis Research

描述(申请人提供)：骨质疏松症是一个主要的健康问题，每年影响近150万人。男性和女性性激素水平的降低都会增加某些导致骨质疏松症的因素的产生。三分之一的更年期妇女一生中至少经历过一次骨质疏松性骨折。此外，某些恶性肿瘤，包括乳房、俯卧或肺，经常转移到长骨、脊柱和/或骨盆。仅在美国，涉及骨骼的原发和转移癌症每年约有40万新发癌症病例，70%的晚期乳腺癌或前列腺癌患者有骨骼转移。持续的破骨细胞活动似乎与持续的和运动诱发的疼痛的产生和维持有关。最近，一些蛋白质因子，如RANK、RANKL和OPG已被确定在疾病的发病机制中起重要作用。RANKL通过与破骨前体细胞表面受体RANK结合，诱导破骨细胞的形成，参与骨吸收。OPG(作为RANKL的诱饵受体)的应用已被证明可以阻止进一步的骨破坏，减少持续的和运动诱发的疼痛。通过抑制分子阻断RANKL正在进行的破骨细胞活性，有可能减轻晚期肿瘤引起的骨破坏患者的骨癌疼痛。由于OPG/RANKL比值在破骨细胞发育中起着重要作用，因此监测患者血液循环中RANKL和OPG的水平具有重要意义。在这项第二阶段的研究中，我们建议使用单克隆抗体，开发灵敏的检测方法来检测血流中的OPG和RANKL。我们还建议开发能够中和破骨细胞发育过程中RANKL活性的单抗，这些单抗将具有治疗应用价值。

DESCRIPTION (provided by applicant): Osteoporosis is a major health problem affecting nearly 1.5 million people every year. The reduction of sex hormone levels in both men and women increase production of certain factors that lead to osteoporosis. One-third of all menopausal women experience at least one osteoporotic fracture during their lifetime. In addition, certain malignancies, including breast, prostrate, or lung frequently metastasize to long bones, spinal vertebrae, and/or pelvis. Primary and metastatic cancers involving bone account for approximately 400,000 new cancer cases per year in the United States alone, and >70% of patients with advanced breast or prostate cancer have skeletal metastases. Ongoing osteoclastic activity appears to be involved in the generation and maintenance of ongoing and movement-evoked pain. Recently, several protein factors, such as RANK, RANKL, and OPG have been identified that are important in the pathogenesis of disease. RANKL by binding to cell surface receptor RANK on the osteoclastic precursor cells induce formation of osteoclasts, which are involved in bone resorption. Administration of OPG (which acts as decoy receptor for RANKL) has been shown to halt further bone destruction, reduce a ongoing and movement-evoked pain. Blockade of ongoing osteoclast activity of RANKL by inhibitory molecules have the potential to reduce bone cancer pain in patients with advanced tumor-induced bone destruction. Since OPG/RANKL ratio play an important role osteoclast development, it is important to monitor the levels of RANKL and OPG in patients' blood circulation. In this Phase II study, using monoclonal antibodies, we propose to develop sensitive assays to measure OPG and RANKL in blood stream. We also propose to develop monoclonal antibodies that can neutralize RANKL activity in the development of osteoclasts, These monoclonal antibodies will have therapeutic application.