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 [Cardiovascular]

Publication Date:
2018-04-04
Publisher:
The American Society for Pharmacology and Experimental Therapeutics
Print ISSN:
0022-3565
Electronic ISSN:
1521-0103
Topics:
Medicine
Published by:
http://www.aspet.org/
_version_ 1836398876905439232
autor Masuda, Y., Yamaguchi, S., Suzuki, C., Aburatani, T., Nagano, Y., Miyauchi, R., Suzuki, E., Yamamura, N., Nagatomo, K., Ishihara, H., Okuno, K., Nara, F., Matschiner, G., Hashimoto, R., Takahashi, T., Nishizawa, T.
beschreibung 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.
citation_standardnr 6225118
datenlieferant ipn_articles
feed_id 1930
feed_publisher The American Society for Pharmacology and Experimental Therapeutics
feed_publisher_url http://www.aspet.org/
insertion_date 2018-04-04
journaleissn 1521-0103
journalissn 0022-3565
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher The American Society for Pharmacology and Experimental Therapeutics
quelle Journal of Pharmacology and Experimental Therapeutics
relation http://jpet.aspetjournals.org/cgi/content/short/365/2/368?rss=1
search_space articles
shingle_author_1 Masuda, Y., Yamaguchi, S., Suzuki, C., Aburatani, T., Nagano, Y., Miyauchi, R., Suzuki, E., Yamamura, N., Nagatomo, K., Ishihara, H., Okuno, K., Nara, F., Matschiner, G., Hashimoto, R., Takahashi, T., Nishizawa, T.
shingle_author_2 Masuda, Y., Yamaguchi, S., Suzuki, C., Aburatani, T., Nagano, Y., Miyauchi, R., Suzuki, E., Yamamura, N., Nagatomo, K., Ishihara, H., Okuno, K., Nara, F., Matschiner, G., Hashimoto, R., Takahashi, T., Nishizawa, T.
shingle_author_3 Masuda, Y., Yamaguchi, S., Suzuki, C., Aburatani, T., Nagano, Y., Miyauchi, R., Suzuki, E., Yamamura, N., Nagatomo, K., Ishihara, H., Okuno, K., Nara, F., Matschiner, G., Hashimoto, R., Takahashi, T., Nishizawa, T.
shingle_author_4 Masuda, Y., Yamaguchi, S., Suzuki, C., Aburatani, T., Nagano, Y., Miyauchi, R., Suzuki, E., Yamamura, N., Nagatomo, K., Ishihara, H., Okuno, K., Nara, F., Matschiner, G., Hashimoto, R., Takahashi, T., Nishizawa, T.
shingle_catch_all_1 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 [Cardiovascular]
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.
Masuda, Y., Yamaguchi, S., Suzuki, C., Aburatani, T., Nagano, Y., Miyauchi, R., Suzuki, E., Yamamura, N., Nagatomo, K., Ishihara, H., Okuno, K., Nara, F., Matschiner, G., Hashimoto, R., Takahashi, T., Nishizawa, T.
The American Society for Pharmacology and Experimental Therapeutics
0022-3565
00223565
1521-0103
15210103
shingle_catch_all_2 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 [Cardiovascular]
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.
Masuda, Y., Yamaguchi, S., Suzuki, C., Aburatani, T., Nagano, Y., Miyauchi, R., Suzuki, E., Yamamura, N., Nagatomo, K., Ishihara, H., Okuno, K., Nara, F., Matschiner, G., Hashimoto, R., Takahashi, T., Nishizawa, T.
The American Society for Pharmacology and Experimental Therapeutics
0022-3565
00223565
1521-0103
15210103
shingle_catch_all_3 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 [Cardiovascular]
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.
Masuda, Y., Yamaguchi, S., Suzuki, C., Aburatani, T., Nagano, Y., Miyauchi, R., Suzuki, E., Yamamura, N., Nagatomo, K., Ishihara, H., Okuno, K., Nara, F., Matschiner, G., Hashimoto, R., Takahashi, T., Nishizawa, T.
The American Society for Pharmacology and Experimental Therapeutics
0022-3565
00223565
1521-0103
15210103
shingle_catch_all_4 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 [Cardiovascular]
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.
Masuda, Y., Yamaguchi, S., Suzuki, C., Aburatani, T., Nagano, Y., Miyauchi, R., Suzuki, E., Yamamura, N., Nagatomo, K., Ishihara, H., Okuno, K., Nara, F., Matschiner, G., Hashimoto, R., Takahashi, T., Nishizawa, T.
The American Society for Pharmacology and Experimental Therapeutics
0022-3565
00223565
1521-0103
15210103
shingle_title_1 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 [Cardiovascular]
shingle_title_2 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 [Cardiovascular]
shingle_title_3 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 [Cardiovascular]
shingle_title_4 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 [Cardiovascular]
timestamp 2025-06-30T23:34:03.062Z
titel 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 [Cardiovascular]
titel_suche 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 [Cardiovascular]
topic WW-YZ
uid ipn_articles_6225118