End-Organ Disease Laboratories (Y.M., Y.N., T.N.), Venture Science Laboratories (S.Y.), Modality Research Laboratories (C.S., T.A., R.M., R.H., T.T.), Drug Metabolism & Pharmacokinetics Research Laboratories (E.S., N.Y.), Biologics Technology Research Laboratories (K.N., H.I., K.O.), and Biologics & Immuno-Oncology Laboratories (F.N.), Daiichi Sankyo Co., Ltd., Tokyo, Japan; and Pieris Pharmaceuticals GmbH, Freising, Germany (G.M.).
End-Organ Disease Laboratories (Y.M., Y.N., T.N.), Venture Science Laboratories (S.Y.), Modality Research Laboratories (C.S., T.A., R.M., R.H., T.T.), Drug Metabolism & Pharmacokinetics Research Laboratories (E.S., N.Y.), Biologics Technology Research Laboratories (K.N., H.I., K.O.), and Biologics & Immuno-Oncology Laboratories (F.N.), Daiichi Sankyo Co., Ltd., Tokyo, Japan; and Pieris Pharmaceuticals GmbH, Freising, Germany (G.M.)
J Pharmacol Exp Ther. 2018 May;365(2):368-378. doi: 10.1124/jpet.117.246652. Epub 2018 Feb 20.
Since it was recently reported that an antibody for proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces the risk of cardiovascular events in a clinical context, PCSK9 inhibition is thought to be an attractive therapy for dyslipidemia. In the present study, we created a novel small biologic alternative to PCSK9 antibodies called DS-9001a, comprising an albumin binding domain fused to an artificial lipocalin mutein (ABD-fused Anticalin protein), which can be produced by a microbial production system. DS-9001a strongly interfered with PCSK9 binding to low-density-lipoprotein receptor (LDL-R) and PCSK9-mediated degradation of LDL-R. In cynomolgus monkeys, single DS-9001a administration significantly reduced the serum LDL-C level up to 21 days (62.4% reduction at the maximum). Moreover, DS-9001a reduced plasma non-high-density-lipoprotein cholesterol and oxidized LDL levels, and their further reductions were observed when atorvastatin and DS-9001a were administered in combination in human cholesteryl ester transfer protein/ApoB double transgenic mice. Additionally, their reductions on the combination of atorvastatin and DS-9001a were more pronounced than those on the combination of atorvastatin and anacetrapib. Besides its favorable pharmacologic profile, DS-9001a has a lower molecular weight (about 22 kDa), yielding a high stoichiometric drug concentration that might result in a smaller administration volume than that in existing antibody therapy. Since bacterial production systems are viewed as more suited to mass production at low cost, DS-9001a may provide a new therapeutic option to treat patients with dyslipidemia. In addition, considering the growing demand for antibody-like drugs, ABD-fused Anticalin proteins could represent a promising new class of small biologic molecules.
由于最近有报道称，前蛋白转化酶枯草溶菌素/ kexin 9 型（PCSK9）的抗体可降低临床心血管事件的风险，因此 PCSK9 抑制被认为是治疗血脂异常的一种有吸引力的治疗方法。在本研究中，我们开发了一种新型的 PCSK9 抗体替代物，称为 DS-9001a，它由白蛋白结合域融合到人工脂蛋白沉默突变体（ABD 融合 Anticalin 蛋白）组成，可通过微生物生产系统生产。DS-9001a 可强烈干扰 PCSK9 与低密度脂蛋白受体（LDL-R）的结合以及 PCSK9 介导的 LDL-R 降解。在食蟹猴中，单次给予 DS-9001a 可使血清 LDL-C 水平显著降低长达 21 天（最大降低 62.4%）。此外，DS-9001a 降低了血浆非高密度脂蛋白胆固醇和氧化 LDL 水平，当阿托伐他汀和 DS-9001a 联合用于人胆固醇酯转移蛋白/载脂蛋白 B 双转基因小鼠时，观察到其进一步降低。此外，与阿托伐他汀和 anacetrapib 联合使用相比，联合使用阿托伐他汀和 DS-9001a 时的降低更为明显。除了其有利的药理特性外，DS-9001a 的分子量较低（约 22 kDa），产生较高的药物浓度，与现有抗体疗法相比，可能需要的给药体积更小。由于细菌生产系统被认为更适合于低成本的大规模生产，因此 DS-9001a 可能为治疗血脂异常的患者提供新的治疗选择。此外，考虑到对抗体样药物的需求不断增长，ABD 融合 Anticalin 蛋白可能代表一类有前途的新型小分子生物药物。
