Abstract
Proprotein convertase substilisin/kexin type 9 (PCSK9) promotes the degradation of low-density lipoprotein (LDL) receptor (LDLR) and thereby increases serum LDL-cholesterol (LDL-C). We have developed a humanized monoclonal antibody that recognizes the LDLR binding domain of PCSK9. This antibody, J16, and its precursor mouse antibody, J10, potently inhibit PCSK9 binding to the LDLR extracellular domain and PCSK9-mediated down-regulation of LDLR in vitro. In vivo, J10 effectively reduces serum cholesterol in C57BL/6 mice fed normal chow. J16 reduces LDL-C in healthy and diet-induced hypercholesterolemic cynomologous monkeys, but does not significantly affect high-density lipoprotein-cholesterol. Furthermore, J16 greatly lowered LDL-C in hypercholesterolemic monkeys treated with the HMG-CoA reductase inhibitor simvastatin. Our data demonstrate that anti-PCSK9 antibody is a promising LDL-C-lowering agent that is both efficacious and potentially additive to current therapies.
Footnotes
This work was supported by Pfizer Inc.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- PCSK9
- proprotein convertase substilisin/kexin type 9
- PCSK9(−/−)
- PCSK9 knockout
- huPCSK9
- human PCSK9
- LDL
- low-density lipoprotein
- LDLR
- LDL receptor
- LDL-C
- LDL-cholesterol
- ECD
- extracellular domain
- HDL
- high-density lipoprotein
- HDL-C
- HDL-cholesterol
- HC
- high cholesterol
- HF
- high fat
- TC
- total cholesterol
- EGF-A
- epidermal growth factor-like repeat A
- NHP
- nonhuman primate
- ELISA
- enzyme-linked immunosorbent assay.
- Received August 29, 2011.
- Accepted October 11, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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