An anti-PCSK9 antibody reduces LDL-cholesterol on top of a statin and suppresses hepatocyte SREBP-regulated genes.
An anti-PCSK9 antibody reduces LDL-cholesterol on top of a statin and suppresses hepatocyte SREBP-regulated genes.
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DOI：
10.7150/ijbs.3524
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发表时间：
2012
影响因子：
9.2
通讯作者：
Sitlani A
中科院分区：
文献类型：
--
作者：
Zhang L;McCabe T;Condra JH;Ni YG;Peterson LB;Wang W;Strack AM;Wang F;Pandit S;Hammond H;Wood D;Lewis D;Rosa R;Mendoza V;Cumiskey AM;Johns DG;Hansen BC;Shen X;Geoghagen N;Jensen K;Zhu L;Wietecha K;Wisniewski D;Huang L;Zhao JZ;Ernst R;Hampton R;Haytko P;Ansbro F;Chilewski S;Chin J;Mitnaul LJ;Pellacani A;Sparrow CP;An Z;Strohl W;Hubbard B;Plump AS;Blom D;Sitlani A
枯草杆菌前蛋白转换酶9(PCSK9)是治疗冠心病的一个有前景的治疗靶点。我们报道了一种新的抗体1B20，它以亚纳摩尔亲和力结合到PCSK9上，并在体外拮抗PCSK9的功能。在CETP/LDLR-HEMI小鼠中，连续两次注射1B20，间隔14天，以3或10MPK给药，诱导低密度脂蛋白胆固醇的剂量依赖性降低(7-14天≥为25%)，这与抗体占据PCSK9的程度密切相关。此外，1B20还可诱导血浆总抗体结合PCSK9水平升高，肝脏SREBP调节基因PCSK9和LDLR的mRNA水平下降，其时间过程与血浆低密度脂蛋白-胆固醇(LDL-C)下降同步。在小鼠身上的观察结果与此一致，在他汀类反应性人原代肝细胞中，1B20降低了PCSK9和LDLR的mRNA水平，并提高了抗体结合的PCSK9的血清稳态水平。此外，经原代人肝细胞抗体处理后，ACSS2、FDPS、IDI1、MVD、HMGCR和CYP51A1等几个参与胆固醇和脂肪酸合成的SREBP调控基因的mRNA水平显著降低。在恒河猴中，皮下注射1B20剂量依赖地诱导强烈的低密度脂蛋白-C降低(最大~70%)，这与靶向参与度和总抗体结合PCSK9水平的增加有关。重要的是，1B20和辛伐他汀联合治疗血脂紊乱的恒河猴比单独使用任何一种药物更能降低低密度脂蛋白-C，这与预测抗PCSK9药物与他汀类药物相加的作用机制是一致的。我们的结果表明，针对PCSK9的抗体可以在他汀类药物的基础上为患者提供强大的降低低密度脂蛋白的效果，并降低心血管风险。
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising therapeutic target for treating coronary heart disease. We report a novel antibody 1B20 that binds to PCSK9 with sub-nanomolar affinity and antagonizes PCSK9 function in-vitro. In CETP/LDLR-hemi mice two successive doses of 1B20, administered 14 days apart at 3 or 10 mpk, induced dose dependent reductions in LDL-cholesterol (≥ 25% for 7-14 days) that correlated well with the extent of PCSK9 occupancy by the antibody. In addition, 1B20 induces increases in total plasma antibody-bound PCSK9 levels and decreases in liver mRNA levels of SREBP-regulated genes PCSK9 and LDLR, with a time course that parallels decreases in plasma LDL-cholesterol (LDL-C). Consistent with this observation in mice, in statin-responsive human primary hepatocytes, 1B20 lowers PCSK9 and LDLR mRNA levels and raises serum steady-state levels of antibody-bound PCSK9. In addition, mRNA levels of several SREBP regulated genes involved in cholesterol and fatty-acid synthesis including ACSS2, FDPS, IDI1, MVD, HMGCR, and CYP51A1 were decreased significantly with antibody treatment of primary human hepatocytes. In rhesus monkeys, subcutaneous (SC) dosing of 1B20 dose-dependently induces robust LDL-C lowering (maximal ~70%), which is correlated with increases in target engagement and total antibody-bound PCSK9 levels. Importantly, a combination of 1B20 and Simvastatin in dyslipidemic rhesus monkeys reduced LDL-C more than either agent alone, consistent with a mechanism of action that predicts additive effects of anti-PCSK9 agents with statins. Our results suggest that antibodies targeting PCSK9 could provide patients powerful LDL lowering efficacy on top of statins, and lower cardiovascular risk.
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影响因子：
9.8
作者：
Ding, Shi-Ying;Tigno, Xenia T.;Hansen, Barbara C.
通讯作者：
Hansen, Barbara C.
影响因子：
6.5
作者：
Dong, Bin;Wu, Minhao;Liu, Jingwen
通讯作者：
Liu, Jingwen
影响因子：
2.8
作者：
Fiegenbaum, M;Silveira, FR;Hutz, MH
通讯作者：
Hutz, MH
DOI：
10.1073/pnas.0903849106
发表时间：
2009-06-16
影响因子：
11.1
作者：
Chan, Joyce C. Y.;Piper, Derek E.;Jackson, Simon M.
通讯作者：
Jackson, Simon M.
DOI：
10.2174/187153008786848286
发表时间：
2008-12-01
影响因子：
1.9
作者：
Cao, Guoqing;Qian, Yue-Wei;Konrad, Robert J.
通讯作者：
Konrad, Robert J.