From CSL Limited, Parkville, Victoria, Australia (A.G.); and CSL Behring, King of Prussia, PA (R.E., D.D., S.D.W., C.L.S.).
Arterioscler Thromb Vasc Biol. 2014 Sep;34(9):2106-14. doi: 10.1161/ATVBAHA.114.303720. Epub 2014 Jun 26.
The ability of apolipoprotein A-I (apoA-I) to transport cholesterol from atherosclerotic plaque is thought to underlie its inverse correlation with cardiovascular risk. To gauge the potential of infused apoA-I to transport cholesterol, we quantified cholesterol transport markers in human subjects infused with a novel formulation of apoA-I (CSL112).
CSL112 was infused into human subjects in single (57 subjects) and multiple (36 subjects) ascending dose trials. Pharmacokinetic and biomarker assessments were conducted before and after infusions. CSL112 caused an immediate, up to 3-fold elevation of apoA-I and subsequent movement of tissue cholesterol into plasma. Cholesterol appeared first as unesterified cholesterol in the high-density lipoprotein (HDL) fraction and was promptly esterified by lecithin cholesterol acyltransferase. HDL cholesterol increased up to 81±16.5%. Underlying this movement of cholesterol was an immediate and strong rise in the ability of plasma to promote cholesterol efflux from cells ex vivo. CSL112 had its greatest impact on the fraction of efflux mediated by ATP-binding cassette transporter A1 (ABCA1), a cholesterol transporter induced in cholesterol-loaded tissues such as plaque. ABCA1-dependent efflux capacity increased ≤630±421% and total efflux capacity by ≤192±40%. In keeping with this finding, we observed a profound rise in very small HDL, also known as preβ1-HDL, the preferred substrate for ABCA1. Very small HDL increased ≤3596±941%. Elevations in apoA-I, cholesterol efflux, and very small HDL were dose-proportional over a wide range. No significant changes in atherogenic lipids were observed at any dose.
Infusion of CSL112 elevates the ability of plasma to withdraw cholesterol from cells. Preferential elevation of ABCA1-dependent efflux may target atherosclerotic plaque for cholesterol removal, making CSL112 a promising candidate therapy for acute coronary syndrome.
载脂蛋白 A-I（apoA-I）将胆固醇从动脉粥样硬化斑块中转运的能力被认为是其与心血管风险呈负相关的基础。为了评估输注 apoA-I 转运胆固醇的潜力，我们对输注新型 apoA-I（CSL112）的人体进行了胆固醇转运标志物的定量。
CSL112 在单次（57 例）和多次（36 例）递增剂量试验中输注到人体中。输注前后进行药代动力学和生物标志物评估。CSL112 立即引起 apoA-I 增加 3 倍，随后组织胆固醇转移到血浆中。胆固醇首先以未酯化胆固醇的形式出现在高密度脂蛋白（HDL）部分，并立即被卵磷脂胆固醇酰基转移酶酯化。HDL 胆固醇增加了 81±16.5%。这种胆固醇转移的基础是血浆促进细胞外胆固醇流出的能力立即而强烈地增加。CSL112 对载脂蛋白 A1（ABCA1）介导的流出部分的影响最大，ABCA1 是胆固醇负载组织（如斑块）中诱导的胆固醇转运蛋白。ABCA1 依赖性流出能力增加≤630±421%，总流出能力增加≤192±40%。与这一发现一致，我们观察到非常小的 HDL（也称为 preβ1-HDL）的急剧增加，preβ1-HDL 是 ABCA1 的首选底物。非常小的 HDL 增加≤3596±941%。在广泛的范围内，apoA-I、胆固醇流出和非常小的 HDL 的升高与剂量成正比。在任何剂量下都没有观察到致动脉粥样硬化脂质的显著变化。
CSL112 的输注可提高血浆从细胞中提取胆固醇的能力。优先升高 ABCA1 依赖性流出可能使动脉粥样硬化斑块成为胆固醇清除的靶点，使 CSL112 成为急性冠状动脉综合征有前途的候选治疗药物。
