PT  - JOURNAL ARTICLE
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
TI  - Generation and Characterization of a Novel Small Biologic Alternative to PCSK9 Antibodies, DS-9001a, Albumin Binding Domain-Fused Anticalin Protein
AID  - 10.1124/jpet.117.246652
DP  - 2018 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.117.246652
4099  - http://jpet.aspetjournals.org/content/early/2018/02/20/jpet.117.246652.short
4100  - http://jpet.aspetjournals.org/content/early/2018/02/20/jpet.117.246652.full
AB  - Since it was recently reported that an antibody for proprotein convertase subtilisin/kexin type 9 (PCSK9) reduced 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 administration of DS-9001a reduced the serum LDL-C level by about 62.4% for more than 21 days. 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 CETP/ApoB double transgenic mice. Additionally, their reductions upon the combination of atorvastatin and DS-9001a were more pronounced than those upon the combination of atorvastatin and anacetrapib. Besides its favorable pharmacological 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 a large number of 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 biological molecules.