Treatment with a human recombinant monoclonal IgG antibody against oxidized LDL in atherosclerosis-prone pigs reduces cathepsin S in coronary lesions

Christian Bo Poulsen; Ahmed Ludvigsen Al-Mashhadi; Karin von Wachenfeldt; Jacob Fog Bentzon; Lars Bo Nielsen; Rozh H Al-Mashhadi; Jesper Thygesen; Lars Tolbod; Jens Rolighed Larsen; Jørgen Frøkiær; Ahmed Tawakol; Esad Vucic; Jill Fredrickson; Amos Baruch; Björn Frendéus; Anna-Karin L Robertson; Søren Kragh Moestrup; Ludovic Drouet; Erling Falk

doi:10.1016/j.ijcard.2016.03.222

Treatment with a human recombinant monoclonal IgG antibody against oxidized LDL in atherosclerosis-prone pigs reduces cathepsin S in coronary lesions

Christian Bo Poulsen, Ahmed Ludvigsen Al-Mashhadi, Karin von Wachenfeldt, Jacob Fog Bentzon, Lars Bo Nielsen, Rozh H Al-Mashhadi, Jesper Thygesen, Lars Tolbod, Jens Rolighed Larsen, Jørgen Frøkiær, Ahmed Tawakol, Esad Vucic, Jill Fredrickson, Amos Baruch, Björn Frendéus, Anna-Karin L Robertson, Søren Kragh Moestrup, Ludovic Drouet, Erling Falk

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

18 Citationer (Scopus)

Abstract

BACKGROUND: Immunization with oxidized LDL (oxLDL) reduces atherosclerosis in rodents. We tested the hypothesis that treatment with a human recombinant monoclonal antibody against oxLDL will reduce the burden or composition of atherosclerotic lesions in hypercholesterolemic minipigs.

METHODS AND RESULTS: Thirty-eight hypercholesterolemic minipigs with defective LDL receptors were injected with an oxLDL antibody or placebo weekly for 12weeks. An 18F-fluorodeoxyglucose positron emission tomography (FDG PET) scan (n=9) was performed before inclusion and after 3months of treatment. Blood samples were obtained prior to each injection. Following the last injection all animals were sacrificed, and the heart, aorta, and iliac arteries were removed. The left anterior descending coronary artery was sectioned at 5mm intervals for quantitative and qualitative assessments of atherosclerosis, including immunohistochemical phenotyping of macrophages using a pan-macrophage marker (CD68) and markers for putative pro-atherogenic (cathepsin S) and atheroprotective (CD163) macrophages. Aorta, right coronary artery, and left iliac artery were stained en face with Sudan IV and the amount of atherosclerosis quantified. There was no effect of treatment on plasma lipid profile, vascular FDG-PET signal or the amount of atherosclerosis in any of the examined arteries. However, immunostaining of coronary lesions revealed reduced cathepsin S positivity in the treated group compared with placebo (4.8% versus 8.2% of intima area, p=0.03) with no difference in CD68 or CD163 positivity.

CONCLUSIONS: In hypercholesterolemic minipigs, treatment with a human recombinant monoclonal antibody against oxLDL reduced cathepsin S in coronary lesions without any effect on the burden of atherosclerosis or aortic FDG-PET signal.

Originalsprog	Engelsk
Tidsskrift	International Journal of Cardiology
Vol/bind	215
Sider (fra-til)	506-515
Antal sider	10
ISSN	0167-5273
DOI	https://doi.org/10.1016/j.ijcard.2016.03.222
Status	Udgivet - 2 apr. 2016

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10.1016/j.ijcard.2016.03.222

Citationsformater

Poulsen, C. B., Al-Mashhadi, A. L., von Wachenfeldt, K., Bentzon, J. F., Nielsen, L. B., Al-Mashhadi, R. H., Thygesen, J., Tolbod, L., Larsen, J. R., Frøkiær, J., Tawakol, A., Vucic, E., Fredrickson, J., Baruch, A., Frendéus, B., Robertson, A.-K. L., Moestrup, S. K., Drouet, L., & Falk, E. (2016). Treatment with a human recombinant monoclonal IgG antibody against oxidized LDL in atherosclerosis-prone pigs reduces cathepsin S in coronary lesions. International Journal of Cardiology, 215, 506-515. https://doi.org/10.1016/j.ijcard.2016.03.222

@article{adf82881b41941708215791318efe621,

title = "Treatment with a human recombinant monoclonal IgG antibody against oxidized LDL in atherosclerosis-prone pigs reduces cathepsin S in coronary lesions",

abstract = "BACKGROUND: Immunization with oxidized LDL (oxLDL) reduces atherosclerosis in rodents. We tested the hypothesis that treatment with a human recombinant monoclonal antibody against oxLDL will reduce the burden or composition of atherosclerotic lesions in hypercholesterolemic minipigs.METHODS AND RESULTS: Thirty-eight hypercholesterolemic minipigs with defective LDL receptors were injected with an oxLDL antibody or placebo weekly for 12weeks. An 18F-fluorodeoxyglucose positron emission tomography (FDG PET) scan (n=9) was performed before inclusion and after 3months of treatment. Blood samples were obtained prior to each injection. Following the last injection all animals were sacrificed, and the heart, aorta, and iliac arteries were removed. The left anterior descending coronary artery was sectioned at 5mm intervals for quantitative and qualitative assessments of atherosclerosis, including immunohistochemical phenotyping of macrophages using a pan-macrophage marker (CD68) and markers for putative pro-atherogenic (cathepsin S) and atheroprotective (CD163) macrophages. Aorta, right coronary artery, and left iliac artery were stained en face with Sudan IV and the amount of atherosclerosis quantified. There was no effect of treatment on plasma lipid profile, vascular FDG-PET signal or the amount of atherosclerosis in any of the examined arteries. However, immunostaining of coronary lesions revealed reduced cathepsin S positivity in the treated group compared with placebo (4.8% versus 8.2% of intima area, p=0.03) with no difference in CD68 or CD163 positivity.CONCLUSIONS: In hypercholesterolemic minipigs, treatment with a human recombinant monoclonal antibody against oxLDL reduced cathepsin S in coronary lesions without any effect on the burden of atherosclerosis or aortic FDG-PET signal.",

author = "Poulsen, {Christian Bo} and Al-Mashhadi, {Ahmed Ludvigsen} and {von Wachenfeldt}, Karin and Bentzon, {Jacob Fog} and Nielsen, {Lars Bo} and Al-Mashhadi, {Rozh H} and Jesper Thygesen and Lars Tolbod and Larsen, {Jens Rolighed} and J{\o}rgen Fr{\o}ki{\ae}r and Ahmed Tawakol and Esad Vucic and Jill Fredrickson and Amos Baruch and Bj{\"o}rn Frend{\'e}us and Robertson, {Anna-Karin L} and Moestrup, {S{\o}ren Kragh} and Ludovic Drouet and Erling Falk",

note = "Copyright {\textcopyright} 2016. Published by Elsevier Ireland Ltd.",

year = "2016",

month = apr,

day = "2",

doi = "10.1016/j.ijcard.2016.03.222",

language = "English",

volume = "215",

pages = "506--515",

journal = "International Journal of Cardiology",

issn = "0167-5273",

publisher = "Elsevier Ireland Ltd",

}

Poulsen, CB, Al-Mashhadi, AL, von Wachenfeldt, K, Bentzon, JF, Nielsen, LB, Al-Mashhadi, RH, Thygesen, J, Tolbod, L , Larsen, JR , Frøkiær, J, Tawakol, A, Vucic, E, Fredrickson, J, Baruch, A, Frendéus, B, Robertson, A-KL, Moestrup, SK, Drouet, L & Falk, E 2016, 'Treatment with a human recombinant monoclonal IgG antibody against oxidized LDL in atherosclerosis-prone pigs reduces cathepsin S in coronary lesions', International Journal of Cardiology, bind 215, s. 506-515. https://doi.org/10.1016/j.ijcard.2016.03.222

Treatment with a human recombinant monoclonal IgG antibody against oxidized LDL in atherosclerosis-prone pigs reduces cathepsin S in coronary lesions. / Poulsen, Christian Bo; Al-Mashhadi, Ahmed Ludvigsen; von Wachenfeldt, Karin et al.
I: International Journal of Cardiology, Bind 215, 02.04.2016, s. 506-515.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

TY - JOUR

T1 - Treatment with a human recombinant monoclonal IgG antibody against oxidized LDL in atherosclerosis-prone pigs reduces cathepsin S in coronary lesions

AU - Poulsen, Christian Bo

AU - Al-Mashhadi, Ahmed Ludvigsen

AU - von Wachenfeldt, Karin

AU - Bentzon, Jacob Fog

AU - Nielsen, Lars Bo

AU - Al-Mashhadi, Rozh H

AU - Thygesen, Jesper

AU - Tolbod, Lars

AU - Larsen, Jens Rolighed

AU - Frøkiær, Jørgen

AU - Tawakol, Ahmed

AU - Vucic, Esad

AU - Fredrickson, Jill

AU - Baruch, Amos

AU - Frendéus, Björn

AU - Robertson, Anna-Karin L

AU - Moestrup, Søren Kragh

AU - Drouet, Ludovic

AU - Falk, Erling

PY - 2016/4/2

Y1 - 2016/4/2

N2 - BACKGROUND: Immunization with oxidized LDL (oxLDL) reduces atherosclerosis in rodents. We tested the hypothesis that treatment with a human recombinant monoclonal antibody against oxLDL will reduce the burden or composition of atherosclerotic lesions in hypercholesterolemic minipigs.METHODS AND RESULTS: Thirty-eight hypercholesterolemic minipigs with defective LDL receptors were injected with an oxLDL antibody or placebo weekly for 12weeks. An 18F-fluorodeoxyglucose positron emission tomography (FDG PET) scan (n=9) was performed before inclusion and after 3months of treatment. Blood samples were obtained prior to each injection. Following the last injection all animals were sacrificed, and the heart, aorta, and iliac arteries were removed. The left anterior descending coronary artery was sectioned at 5mm intervals for quantitative and qualitative assessments of atherosclerosis, including immunohistochemical phenotyping of macrophages using a pan-macrophage marker (CD68) and markers for putative pro-atherogenic (cathepsin S) and atheroprotective (CD163) macrophages. Aorta, right coronary artery, and left iliac artery were stained en face with Sudan IV and the amount of atherosclerosis quantified. There was no effect of treatment on plasma lipid profile, vascular FDG-PET signal or the amount of atherosclerosis in any of the examined arteries. However, immunostaining of coronary lesions revealed reduced cathepsin S positivity in the treated group compared with placebo (4.8% versus 8.2% of intima area, p=0.03) with no difference in CD68 or CD163 positivity.CONCLUSIONS: In hypercholesterolemic minipigs, treatment with a human recombinant monoclonal antibody against oxLDL reduced cathepsin S in coronary lesions without any effect on the burden of atherosclerosis or aortic FDG-PET signal.

AB - BACKGROUND: Immunization with oxidized LDL (oxLDL) reduces atherosclerosis in rodents. We tested the hypothesis that treatment with a human recombinant monoclonal antibody against oxLDL will reduce the burden or composition of atherosclerotic lesions in hypercholesterolemic minipigs.METHODS AND RESULTS: Thirty-eight hypercholesterolemic minipigs with defective LDL receptors were injected with an oxLDL antibody or placebo weekly for 12weeks. An 18F-fluorodeoxyglucose positron emission tomography (FDG PET) scan (n=9) was performed before inclusion and after 3months of treatment. Blood samples were obtained prior to each injection. Following the last injection all animals were sacrificed, and the heart, aorta, and iliac arteries were removed. The left anterior descending coronary artery was sectioned at 5mm intervals for quantitative and qualitative assessments of atherosclerosis, including immunohistochemical phenotyping of macrophages using a pan-macrophage marker (CD68) and markers for putative pro-atherogenic (cathepsin S) and atheroprotective (CD163) macrophages. Aorta, right coronary artery, and left iliac artery were stained en face with Sudan IV and the amount of atherosclerosis quantified. There was no effect of treatment on plasma lipid profile, vascular FDG-PET signal or the amount of atherosclerosis in any of the examined arteries. However, immunostaining of coronary lesions revealed reduced cathepsin S positivity in the treated group compared with placebo (4.8% versus 8.2% of intima area, p=0.03) with no difference in CD68 or CD163 positivity.CONCLUSIONS: In hypercholesterolemic minipigs, treatment with a human recombinant monoclonal antibody against oxLDL reduced cathepsin S in coronary lesions without any effect on the burden of atherosclerosis or aortic FDG-PET signal.

U2 - 10.1016/j.ijcard.2016.03.222

DO - 10.1016/j.ijcard.2016.03.222

M3 - Journal article

C2 - 27135822

SN - 0167-5273

VL - 215

SP - 506

EP - 515

JO - International Journal of Cardiology

JF - International Journal of Cardiology

ER -

Treatment with a human recombinant monoclonal IgG antibody against oxidized LDL in atherosclerosis-prone pigs reduces cathepsin S in coronary lesions

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