HDL mimetic CER-001 targets atherosclerotic plaques in patients.
Infusion of high-density lipoprotein (HDL) mimetics aimed at reducing atherosclerotic burden has led to equivocal results, which may relate in part to the inability of HDL mimetics to adequately reach atherosclerotic lesions in humans. This study evaluated delivery of recombinant human apolipoprotein A-I (apoA-I) containing HDL mimetic CER-001 in carotid plaques in patients.



CER-001 was radiolabeled with the long-lived positron emitter zirconium-89 ((89)Zr) to enable positron emission tomography with computed tomography (PET/CT) imaging. Eight patients with atherosclerotic carotid artery disease (>50% stenosis) received a single infusion of unlabeled CER-001 (3 mg/kg), co-administered with 10 mg of (89)Zr-labeled CER-001 (18 MBq). Serial PET/CT imaging and contrast enhanced-magnetic resonance imaging (CE-MRI) were performed to evaluate targeted delivery of CER-001.



One hour after infusion, mean plasma apoA-I levels increased by 9.9 mg/dL (p = 0.026), with a concomitant relative increase in the plasma cholesterol efflux capacity of 13.8% (p < 0.001). Using serial PET/CT imaging, we showed that arterial uptake of CER-001 expressed as target-to-background ratio (TBRmax) increased significantly 24 h after infusion, and remained increased up to 48 h (TBRmax t = 10 min: 0.98; t = 24 h: 1.14 (p = 0.001); t = 48 h: 1.12 (p = 0.007)). TBRmax was higher in plaque compared with non-plaque segments (1.18 vs. 1.05; p < 0.001). Plaque TBRmax correlated with local plaque contrast enhancement (r = 0.56; p = 0.019) as assessed by CE-MRI.



Infusion of HDL mimetic CER-001 increases plasma apoA-I concentration and plasma cholesterol efflux capacity. Our data support the concept that CER-001 targets plaque regions in patients, which correlates with plaque contrast enhancement. These clinical findings may also guide future nanomedicine development using HDL particles for drug delivery in atherosclerosis.



Netherlands Trial Registry - NTR5178. http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5178.
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: k.h.zheng@amc.nl.
Kang He
KH
Zheng
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: f.m.valkvander@amc.nl.
Fleur M
FM
van der Valk
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: l.p.smits@amc.nl.
Loek P
LP
Smits
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: marasandberg@hotmail.com.
Mara
M
Sandberg
Cerenis Therapeutics Holding, Toulouse, France. Electronic address: dasseux@cerenis.com.
Jean-Louis
JL
Dasseux
Cerenis Therapeutics Holding, Toulouse, France. Electronic address: baron_rudi@yahoo.fr.
Rudi
R
Baron
Cerenis Therapeutics Holding, Toulouse, France. Electronic address: barbaras@cerenis.com.
Ronald
R
Barbaras
Cerenis Therapeutics Holding, Toulouse, France. Electronic address: keyserling@cerenis.com.
Constance
C
Keyserling
Department of Radiology, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: b.f.coolen@amc.nl.
Bram F
BF
Coolen
Department of Radiology, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: a.j.nederveen@amc.nl.
Aart J
AJ
Nederveen
Department of Nuclear Medicine, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: h.j.verberne@amc.nl.
Hein J
HJ
Verberne
Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: t.nell@vumc.nl.
Thijs E
TE
Nell
Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: d.vugts@vumc.nl.
Danielle J
DJ
Vugts
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: raphael.duivenvoorden@gmail.com.
Raphaël
R
Duivenvoorden
Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, USA. Electronic address: zahi.fayad@mssm.edu.
Zahi A
ZA
Fayad
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands; Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, USA. Electronic address: wjmmulder@gmail.com.
Willem J M
WJM
Mulder
Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: GAMS.vanDongen@vumc.nl.
Guus A M S
GAMS
van Dongen
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: e.s.stroes@amc.nl.
Erik S G
ESG
Stroes
D000368:Aged; D016632:Apolipoprotein A-I / Q000737:chemistry*; D003287:Contrast Media / Q000737:chemistry; D004337:Drug Carriers; D005260:Female; D006801:Humans; D008074:Lipoproteins / Q000737:chemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D050997:Nanomedicine; D010743:Phospholipids / Q000737:chemistry*; D058226:Plaque, Atherosclerotic / Q000097:blood* / Q000188:drug therapy* / Q000378:metabolism; D049268:Positron-Emission Tomography; D011994:Recombinant Proteins / Q000737:chemistry*; D014057:Tomography, X-Ray Computed; D015040:Zirconium / Q000737:chemistry
D016632:Apolipoprotein A-I; C000591544:CER-001; D003287:Contrast Media; D004337:Drug Carriers; D008074:Lipoproteins; D010743:Phospholipids; D011994:Recombinant Proteins; D015040:Zirconium
Apolipoprotein A-I; CER-001; HDL mimetic; Imaging; MRI; Nanomedicine; PET/CT; Zirconium-89