TY - JOUR T1 - Generation and Characterization of a Novel Small Biologic Alternative to Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Antibodies, DS-9001a, Albumin Binding Domain–Fused Anticalin Protein JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 368 LP - 378 DO - 10.1124/jpet.117.246652 VL - 365 IS - 2 AU - Yusuke Masuda AU - Shinji Yamaguchi AU - Chikako Suzuki AU - Takahide Aburatani AU - Yuki Nagano AU - Ryuki Miyauchi AU - Eiko Suzuki AU - Naotoshi Yamamura AU - Kentaro Nagatomo AU - Hidetoshi Ishihara AU - Kazuaki Okuno AU - Futoshi Nara AU - Gabriele Matschiner AU - Ryuji Hashimoto AU - Tohru Takahashi AU - Tomohiro Nishizawa Y1 - 2018/05/01 UR - http://jpet.aspetjournals.org/content/365/2/368.abstract N2 - 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. ER -