A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates
A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates
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DOI：
10.1073/pnas.0903849106
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发表时间：
2009-06-16
影响因子：
11.1
通讯作者：
Jackson, Simon M.
中科院分区：
文献类型：
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作者：
Chan, Joyce C. Y.;Piper, Derek E.;Jackson, Simon M.
前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK 9）通过与LDL受体（LDLR）相互作用调节血清LDL胆固醇（LDL-C），是降低LDL-C的有吸引力的治疗靶点。我们已经产生了中和性抗PCSK 9抗体mAb 1，其结合PCSK 9上与LDLR相互作用所需区域相邻的表位。在体外，mAb 1抑制PCSK 9与LDLR结合，并减弱PCSK 9介导的LDLR蛋白水平降低，从而增加LDL摄取。mAb 1与他汀类药物的组合增加HepG 2细胞中的LDLR水平超过任一单独治疗。在野生型小鼠中，mAb 1使肝脏LDLR蛋白水平增加约2倍，并使血清总胆固醇降低高达36%：在LDLR-/-小鼠中未观察到这种作用。在食蟹猴中，单次注射mAb 1可使血清LDL-C降低80%，并持续10天保持显着降低。我们得出结论，抗PCSK 9抗体可能是治疗高胆固醇血症的有效疗法。
Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates serum LDL cholesterol (LDL-C) by interacting with the LDL receptor (LDLR) and is an attractive therapeutic target for LDL-C lowering. We have generated a neutralizing anti-PCSK9 antibody, mAb1, that binds to an epitope on PCSK9 adjacent to the region required for LDLR interaction. In vitro, mAb1 inhibits PCSK9 binding to the LDLR and attenuates PCSK9-mediated reduction in LDLR protein levels, thereby increasing LDL uptake. A combination of mAb1 with a statin increases LDLR levels in HepG2 cells more than either treatment alone. In wild-type mice, mAb1 increases hepatic LDLR protein levels approximate to 2-fold and lowers total serum cholesterol by up to 36%: this effect is not observed in LDLR-/- mice. In cynomolgus monkeys, a single injection of mAb1 reduces serum LDL-C by 80%, and a significant decrease is maintained for 10 days. We conclude that anti-PCSK9 antibodies may be effective therapeutics for treating hypercholesterolemia.