An anti-PCSK9 antibody reduces LDL-cholesterol on top of a statin and suppresses hepatocyte SREBP-regulated genes.

International Journal of Biological Sciences
Liwen ZhangAyesha Sitlani

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising therapeutic target for treating coronary heart disease. We report a novel antibody 1B20 that binds to PCSK9 with sub-nanomolar affinity and antagonizes PCSK9 function in-vitro. In CETP/LDLR-hemi mice two successive doses of 1B20, administered 14 days apart at 3 or 10 mpk, induced dose dependent reductions in LDL-cholesterol (≥ 25% for 7-14 days) that correlated well with the extent of PCSK9 occupancy by the antibody. In addition, 1B20 induces increases in total plasma antibody-bound PCSK9 levels and decreases in liver mRNA levels of SREBP-regulated genes PCSK9 and LDLR, with a time course that parallels decreases in plasma LDL-cholesterol (LDL-C). Consistent with this observation in mice, in statin-responsive human primary hepatocytes, 1B20 lowers PCSK9 and LDLR mRNA levels and raises serum steady-state levels of antibody-bound PCSK9. In addition, mRNA levels of several SREBP regulated genes involved in cholesterol and fatty-acid synthesis including ACSS2, FDPS, IDI1, MVD, HMGCR, and CYP51A1 were decreased significantly with antibody treatment of primary human hepatocytes. In rhesus monkeys, subcutaneous (SC) dosing of 1B20 dose-dependently induces robust LDL-...Continue Reading

References

Nov 19, 2002·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Lorraine SalekA J Marian
May 6, 2003·Nature Genetics·Marianne AbifadelCatherine Boileau
Jan 29, 2005·Proceedings of the National Academy of Sciences of the United States of America·Kara N MaxwellJan L Breslow
Apr 5, 2005·Proceedings of the National Academy of Sciences of the United States of America·Shirya RashidJay D Horton
Feb 9, 2006·American Journal of Human Genetics·Ingrid K KotowskiHelen H Hobbs
Mar 24, 2006·The New England Journal of Medicine·Jonathan C CohenHelen H Hobbs
Mar 31, 2006·Human Molecular Genetics·Jamie CameronTrond P Leren
Nov 3, 2006·The Journal of Clinical Investigation·Thomas A LagaceJay D Horton
Jan 12, 2007·Trends in Biochemical Sciences·Jay D HortonHelen H Hobbs
May 12, 2007·The Journal of Biological Chemistry·Timothy S FisherAyesha Sitlani
Jan 17, 2008·Biochemistry·Daping FanSergio Fazio
Jul 25, 2008·Atherosclerosis·Gilles LambertDerek E Piper
Aug 2, 2008·Trends in Biochemical Sciences·Philippe CostetBertrand Cariou
Aug 13, 2008·Proceedings of the National Academy of Sciences of the United States of America·Maria Frank-KamenetskyKevin Fitzgerald
Aug 30, 2008·Proceedings of the National Academy of Sciences of the United States of America·Da-Wei ZhangHelen H Hobbs
Dec 10, 2008·Expert Opinion on Therapeutic Targets·Nabil G Seidah
Dec 17, 2008·Endocrine, Metabolic & Immune Disorders Drug Targets·Guoqing CaoRobert J Konrad
Feb 7, 2009·The Biochemical Journal·Christopher J DuffNigel M Hooper
Feb 10, 2009·Nature Genetics·UNKNOWN Myocardial Infarction Genetics ConsortiumDavid Altshuler
May 16, 2009·Proceedings of the National Academy of Sciences of the United States of America·Joyce C Y ChanSimon M Jackson
Jul 3, 2009·Journal of Lipid Research·Geneviève DubucJean Davignon
Jul 16, 2009·Recent Patents on DNA & Gene Sequences·Hai LiJingwen Liu
Mar 17, 2010·Pharmacology & Therapeutics·Philippe Costet
Mar 20, 2010·BMC Health Services Research·Peter FranksKevin Fiscella
May 7, 2010·The Journal of Clinical Endocrinology and Metabolism·Robert H Eckel
Jun 1, 2010·Expert Opinion on Pharmacotherapy·Konstantinos ToutouzasChristodoulos Stefanadis
Jul 14, 2010·Archives of Cardiovascular Diseases·Jean FerrièresVanina Bongard
Sep 21, 2010·Expert Opinion on Therapeutic Patents·Marianne AbifadelCatherine Boileau

❮ Previous
Next ❯

Citations

Apr 29, 2014·European Journal of Pharmacology·Thomas P RoddyDouglas G Johns
Oct 17, 2014·Science Translational Medicine·Keith R WalleyJohn H Boyd
Jan 23, 2013·Current Cardiology Reports·Rose Q DoGregory G Schwartz
Oct 8, 2013·Expert Opinion on Therapeutic Patents·Katsuyuki Nakajima, Junji Kobayashi
Sep 4, 2015·Expert Opinion on Biological Therapy·Annukka M KiveläSeppo Ylä-Herttuala
Nov 9, 2015·The American Journal of Cardiology·Arihiro KiyosueAtsushi Hirayama
Jun 10, 2015·Biochemical and Biophysical Research Communications·Yan CaoZhigang Guo
Sep 29, 2015·Vaccine·Erin CrosseyAlan T Remaley
May 15, 2015·European Heart Journal·Yuichi J Shimada, Christopher P Cannon
Apr 13, 2013·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Li ShenShuiping Zhao
Dec 5, 2014·PloS One·Gergana GalabovaGuenther Staffler
Jan 9, 2013·Human Molecular Genetics·Feng GaoRonald M Krauss
Aug 31, 2016·Annual Review of Pharmacology and Toxicology·Amy C BurkeMurray W Huff
Sep 24, 2015·Journal of Lipid Research·Krista M SchroederPatrick I Eacho
Sep 6, 2015·Journal of Lipid Research·Sam J L van der TuinYanan Wang
Mar 16, 2017·World Journal of Cardiology·Rahul ChaudharyAndrew Sumner
Feb 19, 2019·Annals of Internal Medicine·Juan de Dios García-DíazConcepción Hernández-Ahijado
Jun 12, 2012·Nature Reviews. Drug Discovery·Nabil G Seidah, Annik Prat
Dec 25, 2019·Journal of the American Heart Association·Danyu WuZhihua Qiu
Jan 25, 2020·Expert Opinion on Drug Discovery·Etienne KhouryDaniel Gaudet
Aug 22, 2012·Current Opinion in Lipidology·David A MaraisGilles Lambert
Dec 5, 2018·Scientific Reports·Matthieu ChodorgeJane K Osbourn
Oct 4, 2017·Scientific Reports·Yajie PanYuhua Liao
Jun 25, 2014·Nature Reviews. Cardiology·Razvan T Dadu, Christie M Ballantyne
Jun 19, 2014·Journal of Cardiovascular Pharmacology and Therapeutics·Simona DraganMaciej Banach
Aug 15, 2017·Journal of Atherosclerosis and Thrombosis·Tsuyoshi Nozue
Nov 13, 2020·Journal of Bioscience and Bioengineering·Takehiro AndoTakashi Kawakami
Jan 13, 2021·Scientific Reports·Joshua A LevineDouglas E Vaughan
Oct 23, 2020·Liver International : Official Journal of the International Association for the Study of the Liver·Stefania GrimaudoSalvatore Petta
Dec 14, 2018·Pathology·Valentin BlanchardGilles Lambert
Sep 9, 2019·ACS Biomaterials Science & Engineering·Shasha YouBin He
Aug 24, 2021·Current Treatment Options in Rheumatology·Emma Weeding, Eleni Tiniakou

❮ Previous
Next ❯

Methods Mentioned

BETA
surface plasmon resonance
chip
transgenic
ELISA
phage display
enzyme-linked immunosorbent assay
PCR

Software Mentioned

ArrayScan
GraphPad
WinNonlin

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.