Summary

Here, we proposed the use of mutated RANKL as an immunogen for active immunization and to induce anti-cytokine antibodies for osteoporosis treatment.

Introduction

Osteoclasts are responsible for bone resorption in bone-related disorders. Anti-cytokine therapeutic antibodies such as denosumab are effective for the treatment of osteoporosis. However, problems with antibody manufacturing and the immunogenicity caused by multiple antibody doses have led to the use of auto-cytokines as immunogens to induce anti-cytokine antibodies.

Methods

RANKL was point-mutated based on the crystal structure of the complex of RANKL and its receptor RANK.

Results

As a proof of concept, immunization with RANKL produced high levels of specific antibodies and blocked osteoclast development in vitro and inhibited osteoporosis in RANKL-treated or ovariectomized mouse models.

Conclusions

The results demonstrate the successful use of mutated RANKL as an immunogen for the induction of anti-RANKL immune response. This strategy is useful in general anti-cytokine immunotherapy to avoid toxic side effects of osteoporosis treatment.

中文翻译：

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RANKL-RANK结合位点的修饰，用于骨质疏松症的免疫治疗

概要

在这里，我们建议使用突变的RANKL作为免疫原进行主动免疫，并诱导抗细胞因子抗体治疗骨质疏松症。

介绍

破骨细胞负责骨骼相关疾病中的骨骼吸收。抗细胞因子治疗性抗体（例如denosumab）可有效治疗骨质疏松症。然而，由于多次抗体剂量引起的抗体制造和免疫原性的问题已导致使用自体细胞因子作为免疫原来诱导抗细胞因子抗体。

方法

基于RANKL及其受体RANK的复合物的晶体结构，对RANKL进行点突变。

结果

作为概念的证明，在RANKL治疗或卵巢切除的小鼠模型中，用RANKL免疫产生了高水平的特异性抗体，并在体外阻断了破骨细胞的发育并抑制了骨质疏松。

结论

结果证明突变的RANKL成功地用作诱导抗RANKL免疫应答的免疫原。该策略可用于常规抗细胞因子免疫疗法，以避免骨质疏松症治疗的毒性副作用。