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The DOI matches its Crossref record; 5 of the 5 references it cites were found in a registry or an index.

A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates

Chan, Joyce C. Y., Piper, Derek E., Cao, Qiong, Liu, Dongming, King, Chadwick, Wang, Wei, Tang, Jie, Liu, Qiang, Higbee, Jared, Xia, Zhen, Di, Yongmei, Shetterly, Susan, Arimura, Ziva, Salomonis, Heather, Romanow, William G., Thibault, Stephen T., Zhang, Richard, Cao, Ping, Yang, Xiao-Ping, Yu, Timothy, Lu, Mei, Retter, Marc W., Kwon, Gayle, Henne, Kirk, Pan, Oscar, Tsai, Mei-Mei, Fuchslocher, Bryna, Yang, Evelyn, Zhou, Lei, Lee, Ki Jeong, Daris, Mark, Sheng, Jackie, Wang, Yan, Shen, Wenyan D., Yeh, Wen-Chen, Emery, Maurice, Walker, Nigel P. C., Shan, Bei, Schwarz, Margrit, Jackson, Simon M.·2009·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0903849106
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Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates serum LDL cholesterol (LDL-C) by interacting with the LDL receptor (LDLR) and is an attractive therapeutic target for LDL-C lowering. We have generated a neutralizing anti-PCSK9 antibody, mAb1, that binds to an epitope on PCSK9 adjacent to the region required for LDLR interaction. In vitro, mAb1 inhibits PCSK9 binding to the LDLR and attenuates PCSK9-mediated reduction in LDLR protein levels, thereby increasing LDL uptake. A combination of mAb1 with a statin increases LDLR levels in HepG2 cells more than either treatment alone. In wild-type mice, mAb1 increases hepatic LDLR protein levels ≈2-fold and lowers total serum cholesterol by up to 36%: this effect is not observed in LDLR −/− mice. In cynomolgus monkeys, a single injection of mAb1 reduces serum LDL-C by 80%, and a significant decrease is maintained for 10 days. We conclude that anti-PCSK9 antibodies may be effective therapeutics for treating hypercholesterolemia.

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  • Antibody-induced inhibition of Pcsk9 binding to Ldlr is currently investigated as a promising therapy to reduce plasma LDL-cholesterol and atherosclerosis in patients.

    “Antibody-induced inhibition of Pcsk9 binding to Ldlr is currently investigated as a very promising therapy to reduce plasma LDL-cholesterol and atherosclerosis in patients.24,25”

    From The Sirt1 activator SRT3025 provides atheroprotection in Apoe−/− mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression (2015) · cites this paper as [24]

    The Abstract reports that the antibody blocks PCSK9–LDLR binding and lowers LDL cholesterol in monkeys; the Discussion describes its potential as a treatment for patients. The study did not test the antibody in patients or show that it reduces atherosclerosis, so those parts of the claim go beyond this source. (LLM, conf=0.87)

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Research works printed but not linked: 36

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Metadata

Authors
Chan, J. C. Y., Piper, D. E., Cao, Q., Liu, D., King, C., Wang, W., Tang, J., Liu, Q., Higbee, J., Xia, Z., Di, Y., Shetterly, S., Arimura, Z., Salomonis, H., Romanow, W. G., Thibault, S. T., Zhang, R., Cao, P., Yang, X.-P., Yu, T., Lu, M., Retter, M. W., Kwon, G., Henne, K., Pan, O., Tsai, M.-M., Fuchslocher, B., Yang, E., Zhou, L., Lee, K. J., Daris, M., Sheng, J., Wang, Y., Shen, W. D., Yeh, W.-C., Emery, M., Walker, N. P. C., Shan, B., Schwarz, M., & Jackson, S. M.
Affiliations
  • Departments of Metabolic Disorders,
  • Molecular Structure,
  • Department of Protein Science, Amgen Inc., Burnaby, British Columbia V5A 1V7, Canada;
  • Department of Protein Science and
  • Protein Science, and
  • Departments of Pharmacokinetics and Drug Metabolism, Amgen Inc., Seattle, WA 98119
  • Pharmacokinetics and Drug Metabolism, Amgen Inc., South San Francisco, CA 94080;
  • Biostatistics and Epidemiology, Amgen Inc., Thousand Oaks, CA 91320; and
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2009-06-16
Volume
106
Issue
24
Pages
9820-9825
ISSN
  • 0027-8424
  • 1091-6490
DOI
10.1073/pnas.0903849106
Cited by
371
References
5
Language
en

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