Study of the therapeutic vaccine approach targeting RANKL.

我们正在开发一种新的蛋白疫苗，靶向在代谢性骨疾病中异常表达的NFκB配体自蛋白受体激活因子（RANKL）。RANKL（也称为OPGL、TRANCE或ODF）是骨吸收的关键调节因子，也是骨破坏相关疾病的治疗靶点。RANKL是tnf家族的一员，是一种由317个氨基酸组成的II型跨膜蛋白，可作为膜结合蛋白和分泌蛋白表达。活化的T细胞、成骨细胞和部分基质细胞表达RANKL，许多诱导骨吸收的化合物（1α、25 (OH)_2、维生素D_3、PTH、PGE_2、IL-1α、TNFα、IL-11和糖皮质激素）通过增强RANKL的表达而起作用。RANKL刺激破骨细胞分化活化，延长成熟破骨细胞存活时间。骨保护素（OPG）是一种可溶性诱饵受体，可以中和RANKL，并有助于维持骨吸收和形成的平衡。在骨质疏松症、类风湿性关节炎和转移性骨癌中，RANKL -OPG比值的破坏与病理上的骨质破坏有关。中和RANKL在绝经后骨质疏松症、类风湿性关节炎、骨转移、牙周病的动物模型中有效减少骨破坏，并在绝经后妇女和骨转移的I期临床试验中减少骨转换标志物。小鼠RANKL疫苗抑制骨吸收的能力先前在小鼠病理性骨病模型中进行了测试。第一项研究是在绝经后骨质疏松症模型中进行的。小鼠在卵巢切除术（OVX）手术前预先接种小鼠RANKL蛋白疫苗以诱导骨吸收。接受OVX手术后，接种疫苗的对照组小鼠的骨密度（BMD）比接受假手术的小鼠低16%。相比之下，接种RANKL疫苗的小鼠在ovx手术后没有失去小梁骨，与假手术的幼鼠相比。下一个动物实验是在类风湿关节炎模型中进行的。SKG小鼠是Balb/c小鼠的自发突变体，在8周龄时出现类风湿关节炎样症状。RANKL疫苗使活化的成骨细胞募集到受影响关节的比例提高了90%，并使伴随的骨破坏率降低了80%。令人惊讶的是，滑膜炎症平均减少了40%，在一些小鼠中完全消失。少

We are developing a novel protein vaccine targeting the self-protein Receptor Activator of NFκB Ligand (RANKL) aberrantly expressed in metabolic bone disorders. RANKL (also know as OPGL, TRANCE, or ODF) is a key regulator of bone resorption and a therapeutic target for diseases associated with bone destruction. RANKL, a member of the TNF-family, is a 317 amino acid type II transmembrane protein expressed both as a membrane bound and secreted protein. Activated T cells, osteoblasts and some stromal cells express RANKL and many compounds that induce bone resorption (1α,25 (OH)_2 vitamin D_3, PTH, PGE_2, IL-1α, TNFα, IL-11, and glucocorticoids) act by enhancing RANKL expression. RANKL stimulates osteoclast differentiation and activation, as well as prolongs survival of mature osteoclasts. Osteoprotegerin (OPG), a soluble decoy receptor, can neutralize RANKL and helps to maintain the balance of bone resorption and formation. Disruption of the RANKL -OPG ratio is associated with pathologica … More l bone destruction as seen in osteoporosis, rheumatoid arthritis and metastatic bone cancer. Neutralizing RANKL is effective at reducing bone destruction in animal models of postmenopausal osteoporosis, rheumatoid arthritis, bone metastasis, periodontal disease and reducing markers of bone turnover in phase I clinical trials of postmenopausal women and bone metastases. The ability of the murine RANKL vaccine to suppress bone resorption were previously tested in mouse models of pathological bone disease. The first study was conducted in a model of post-menopausal osteoporosis. Mice were pre-vaccinated with a murine RANKL protein vaccine prior to ovariectomy (OVX) surgery to induce bone resorption. After OVX surgery control vaccinated mice had 16% lower bone mineral density (BMD) compared to sham-operated littermates. In contrast mice vaccinated with the murine RANKL vaccine did not lose trabecular bone after OVX-surgery compared to sham-operated littermates. The next animal study was conducted in a model of rheumatoid arthritis. The SKG mouse is a spontaneous mutant of Balb/c mouse that develops rheumatoid arthritis-like symptoms by 8 weeks of age. RANKL vaccinations ameliorated the recruitment of activated osteoblasts to the affected joints by 90% and the accompanying bone destruction by 80%. Surprisingly, the synovial inflammation was on average reduced by 40%, and completely ablated in some of the mice. Less