Immunization against proprotein convertase subtilisin-like/kexin type 9 lowers plasma LDL-cholesterol levels in mice
Immunization against proprotein convertase subtilisin-like/kexin type 9 lowers plasma LDL-cholesterol levels in mice
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DOI：
10.1194/jlr.m028340
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发表时间：
2012-08-01
影响因子：
6.5
通讯作者：
Monaci, Paolo
中科院分区：
文献类型：
--
作者：
Fattori, Elena;Cappelletti, Manuela;Monaci, Paolo
针对新靶点的药物的成功开发关键取决于体内靶基因产物活性的可靠鉴定以及其对疾病发展的特定功能作用的明确证明。在这里，我们描述了一种免疫敲低（IKD）方法，这是一种用于内源基因产物体内验证和功能研究的新方法。该方法依赖于引发针对所选内源靶蛋白的短暂体液反应的能力。抗靶标抗体特异性结合靶标蛋白，其中一部分可有效中和其活性。我们应用 IKD 方法体内验证血浆 PCSK9 作为治疗血浆低密度脂蛋白胆固醇水平升高的潜在靶标。我们发现，在小鼠中使用人 PCSK9 进行免疫能够产生交叉反应并中和循环小鼠 PCSK9 蛋白的抗体，从而导致肝脏 LDL 受体水平和血浆胆固醇摄取增加。这些发现与 PCSK9 敲除小鼠或用通过阻止 PCSK9/LDLR 相互作用来抑制 PCSK9 的抗体治疗的小鼠中描述的结果非常相似。我们的数据支持 IKD 方法作为快速验证新靶蛋白的有效方法。-Fattori, E., M. Cappelletti, P. Lo Surdo, A. Calzetta, C. Bendtsen, Y. G. Ni, S. Pandit, A. Sitlani, G. Mesiti, A. Carf, 和 P. Monaci。针对前蛋白转化酶枯草杆菌蛋白酶样/kexin 9 型的免疫可降低小鼠血浆 LDL 胆固醇水平。 J.脂质研究。 2012。53：1654-1661。
Successful development of drugs against novel targets crucially depends on reliable identification of the activity of the target gene product in vivo and a clear demonstration of its specific functional role for disease development. Here, we describe an immunological knockdown (IKD) method, a novel approach for the in vivo validation and functional study of endogenous gene products. This method relies on the ability to elicit a transient humoral response against the selected endogenous target protein. Anti-target antibodies specifically bind to the target protein and a fraction of them effectively neutralize its activity. We applied the IKD method to the in vivo validation of plasma PCSK9 as a potential target for the treatment of elevated levels of plasma LDL-cholesterol. We show that immunization with human-PCSK9 in mice is able to raise antibodies that cross-react and neutralize circulating mouse-PCSK9 protein thus resulting in increased liver LDL receptor levels and plasma cholesterol uptake. These findings closely resemble those described in PCSK9 knockout mice or in mice treated with antibodies that inhibit PCSK9 by preventing the PCSK9/LDLR interaction. Our data support the IKD approach as an effective method to the rapid validation of new target proteins.-Fattori, E., M. Cappelletti, P. Lo Surdo, A. Calzetta, C. Bendtsen, Y. G. Ni, S. Pandit, A. Sitlani, G. Mesiti, A. Carf, and P. Monaci. Immunization against proprotein convertase subtilisin-like/kexin type 9 lowers plasma LDL-cholesterol levels in mice. J. Lipid Res. 2012. 53: 1654-1661.