Study of the therapeutic vaccine approach targeting RANKL.

我们正在开发一种针对在代谢性骨骼疾病中异常表达的核因子κB配体的自身蛋白受体激活剂(RANKL)的新型蛋白质疫苗。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是肿瘤坏死因子家族的一员，是一种317个氨基酸的II型跨膜蛋白，以膜结合蛋白和分泌型蛋白的形式表达。活化的T细胞、成骨细胞和一些基质细胞表达RANKL，许多诱导骨吸收的化合物(1α、25(OH)2、维生素D3、甲状旁腺素、前列腺素E_2、IL-1α、肿瘤坏死因子α、IL-11和糖皮质激素)通过增强RANKL的表达发挥作用。RANKL可刺激破骨细胞分化和活化，延长成熟破骨细胞的存活时间。护骨素(OPG)是一种可溶性诱饵受体，可中和RANKL，有助于维持骨吸收和骨形成的平衡。RANKL-OPG比例失调与病理性…相关L的骨质破坏多见于骨质疏松症、类风湿性关节炎和转移性骨癌。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，中和RANKL有效地减少骨破坏，并在绝经后妇女和骨转移的I期临床试验中降低骨转换的标志物。小鼠RANKL疫苗抑制骨吸收的能力之前在病理性骨病小鼠模型中进行了测试。第一项研究是在绝经后骨质疏松症模型上进行的。小鼠在卵巢切除(OVX)手术前预先接种小鼠RANKL蛋白疫苗，以诱导骨吸收。OVX手术后，对照组小鼠的骨密度(BMD)比假手术组小鼠低16%。相比之下，与假手术小鼠相比，接种小鼠RANKL疫苗的小鼠在去卵巢手术后没有丢失骨小梁。下一项动物研究是在类风湿性关节炎模型上进行的。SKG小鼠是Balb/c小鼠的自发突变，在8周大时会出现类风湿性关节炎症状。接种RANKL疫苗后，90%的活化成骨细胞重新聚集到病变关节，伴随的骨破坏减少80%。令人惊讶的是，滑膜炎症平均减少了40%，并在一些小鼠身上完全消融。较少

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