HDL mimetic CER-001 targets atherosclerotic plaques in patients

Kang He Zheng; Fleur M. van der Valk; Loek P. Smits; Mara Sandberg; Jean-Louis Dasseux; Rudi Baron; Ronald Barbaras; Constance Keyserling; Bram F. Coolen; Aart J. Nederveen; Hein J. Verberne; Thijs E. Nell; Danielle J. Vugts; Raphaël Duivenvoorden; Zahi A. Fayad; Willem J. M. Mulder; Guus A. M. S. van Dongen; Erik S. G. Stroes

doi:https://doi.org/10.1016/j.atherosclerosis.2016.05.038

HDL mimetic CER-001 targets atherosclerotic plaques in patients

Kang He Zheng, Fleur M. van der Valk, Loek P. Smits, Mara Sandberg, Jean-Louis Dasseux, Rudi Baron, Ronald Barbaras, Constance Keyserling, Bram F. Coolen, Aart J. Nederveen, Hein J. Verberne, Thijs E. Nell, Danielle J. Vugts, Raphaël Duivenvoorden, Zahi A. Fayad, Willem J. M. Mulder, Guus A. M. S. van Dongen, Erik S. G. Stroes

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

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

Original language	English
Pages (from-to)	381-388
Journal	Atherosclerosis
Volume	251
DOIs	https://doi.org/10.1016/j.atherosclerosis.2016.05.038
Publication status	Published - Aug 2016

Keywords

Apolipoprotein A-I
CER-001
HDL mimetic
Imaging
MRI
Nanomedicine
PET/CT
Zirconium-89

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https://doi.org/10.1016/j.atherosclerosis.2016.05.038

Cite this

Zheng, K. H., van der Valk, F. M., Smits, L. P., Sandberg, M., Dasseux, J.-L., Baron, R., Barbaras, R., Keyserling, C., Coolen, B. F., Nederveen, A. J., Verberne, H. J., Nell, T. E., Vugts, D. J., Duivenvoorden, R., Fayad, Z. A., Mulder, W. J. M., van Dongen, G. A. M. S., & Stroes, E. S. G. (2016). HDL mimetic CER-001 targets atherosclerotic plaques in patients. Atherosclerosis, 251, 381-388. https://doi.org/10.1016/j.atherosclerosis.2016.05.038

@article{3cba8fc30db949588fec35e7219463b3,

title = "HDL mimetic CER-001 targets atherosclerotic plaques in patients",

abstract = "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",

keywords = "Apolipoprotein A-I, CER-001, HDL mimetic, Imaging, MRI, Nanomedicine, PET/CT, Zirconium-89",

author = "Zheng, {Kang He} and {van der Valk}, {Fleur M.} and Smits, {Loek P.} and Mara Sandberg and Jean-Louis Dasseux and Rudi Baron and Ronald Barbaras and Constance Keyserling and Coolen, {Bram F.} and Nederveen, {Aart J.} and Verberne, {Hein J.} and Nell, {Thijs E.} and Vugts, {Danielle J.} and Rapha{\"e}l Duivenvoorden and Fayad, {Zahi A.} and Mulder, {Willem J. M.} and {van Dongen}, {Guus A. M. S.} and Stroes, {Erik S. G.}",

year = "2016",

month = aug,

doi = "https://doi.org/10.1016/j.atherosclerosis.2016.05.038",

language = "English",

volume = "251",

pages = "381--388",

journal = "Atherosclerosis",

issn = "0021-9150",

publisher = "Elsevier Ireland Ltd",

}

Zheng, KH, van der Valk, FM, Smits, LP, Sandberg, M, Dasseux, J-L, Baron, R, Barbaras, R, Keyserling, C, Coolen, BF , Nederveen, AJ , Verberne, HJ, Nell, TE, Vugts, DJ, Duivenvoorden, R, Fayad, ZA, Mulder, WJM , van Dongen, GAMS & Stroes, ESG 2016, 'HDL mimetic CER-001 targets atherosclerotic plaques in patients', Atherosclerosis, vol. 251, pp. 381-388. https://doi.org/10.1016/j.atherosclerosis.2016.05.038

TY - JOUR

T1 - HDL mimetic CER-001 targets atherosclerotic plaques in patients

AU - Zheng, Kang He

AU - van der Valk, Fleur M.

AU - Smits, Loek P.

AU - Sandberg, Mara

AU - Dasseux, Jean-Louis

AU - Baron, Rudi

AU - Barbaras, Ronald

AU - Keyserling, Constance

AU - Coolen, Bram F.

AU - Nederveen, Aart J.

AU - Verberne, Hein J.

AU - Nell, Thijs E.

AU - Vugts, Danielle J.

AU - Duivenvoorden, Raphaël

AU - Fayad, Zahi A.

AU - Mulder, Willem J. M.

AU - van Dongen, Guus A. M. S.

AU - Stroes, Erik S. G.

PY - 2016/8

Y1 - 2016/8

N2 - 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

AB - 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

KW - Apolipoprotein A-I

KW - CER-001

KW - HDL mimetic

KW - Imaging

KW - MRI

KW - Nanomedicine

KW - PET/CT

KW - Zirconium-89

U2 - https://doi.org/10.1016/j.atherosclerosis.2016.05.038

DO - https://doi.org/10.1016/j.atherosclerosis.2016.05.038

M3 - Article

C2 - 27263077

SN - 0021-9150

VL - 251

SP - 381

EP - 388

JO - Atherosclerosis

JF - Atherosclerosis

ER -