Effect of repeated apoA-IMilano/POPC infusion on lipids, (apo)lipoproteins, and serum cholesterol efflux capacity in cynomolgus monkeys

Kempen, H.J.M.; Gomaraschi, Monica; Bellibas, S. Eralp; Plassmann, Stephanie; Zerler, Brad; Collins, Heidi L.; Adelman, Steven J.; Calabresi, Laura; Wijngaard, Peter

doi:10.1194/jlr.m033779

Cited by 26 publications

(24 citation statements)

References 61 publications

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“…233 Infusion of MDCO-216 into cynomolgous monkeys increased the capacity of plasma to induce cholesterol efflux via the ABCA1 pathway much more prominently than via the ABCG1 and SR-BI pathways, probably by displacing endogenous wild-type apoA-I from endogenous HDL and thereby enhancing the formation of prebeta1-HDL. 234 A similar effect was seen ex vivo, when MDCO-216 was mixed with human plasma. 235 -CER-001 is the third formulation of rHDL that has entered clinical evaluation in humans.…”

Section: Hdl Mimeticsmentioning

confidence: 65%

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Annema

Eckardstein

2016

Translational Research

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Low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risks of coronary heart disease. HDL mediates cholesterol efflux from macrophages for reverse transport to the liver and elicits many anti-inflammatory and anti-oxidative activities which are potentially antiatherogenic. Nevertheless, HDL has not been successfully targeted by drugs for prevention or treatment of cardiovascular diseases. One potential reason is the targeting of HDL cholesterol which does not capture the structural and functional complexity of HDL particles. Hundreds of lipid species and dozens of proteins as well as several microRNAs have been identified in HDL. This physiological heterogeneity is further increased in pathologic conditions due to additional quantitative and qualitative molecular changes of HDL components which have been associated with both loss of physiological function and gain of pathologic dysfunction. This structural and functional complexity of HDL has prevented clear assignments of molecules to the functions of normal HDL and dysfunctions of pathologic HDL. Systematic analyses of structure-function relationships of HDL-associated molecules and their modifications are needed to test the different components and functions of HDL for their relative contribution in the pathogenesis of atherosclerosis. The derived biomarkers and targets may eventually help to exploit HDL for treatment and diagnostics of cardiovascular diseases.

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Section: Hdl Mimeticsmentioning

confidence: 65%

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Annema

Eckardstein

2016

Translational Research

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“…More recently the same product manufactured by an improved process, called MDCO-216, was shown by us to be safe in a multiple ascending dose toxicity study in cynomolgus monkeys (9). This study also demonstrated strongly elevated free cholesterol (FC) levels and enhanced ABCA1-mediated cholesterol efflux capacity of serum after drug infusion, accompanied by a shift of apoE from HDL toward VLDL and LDL (9).…”

Section: Introductionmentioning

confidence: 89%

“…The final product contained 13 mg/ml protein, 14 mg/ml POPC, 1.3 mg/ml di-sodium hydrogen phosphate heptahydrate, 0.178 mg/ml sodium dihydrogen phosphate dehydrate, 62 mg/ml sucrose, 8.2 mg/ml mannitol. Physicochemical properties of the complex were described in detail before (9) and its concentration is expressed as protein content.…”

Section: Drug Productmentioning

confidence: 99%

“…Plasma levels of free and esterified cholesterol, of cholesterol esterification rate (CER) and of lipoprotein lipids and apolipoproteins after separation by FPLC were measured using methods described in detail before (9). In the healthy volunteers only the 20 mg/kg and 40 mg/kg dose groups were analyzed, while in the CAD patients all 4 dose groups except placebo were analyzed.…”

Section: Laboratory Analysesmentioning

confidence: 99%

“…More than 10 years ago repeated infusion of rec-HDL containing apoA-IM (at the time named ETC-216) was shown to cause rapid regression of atherosclerotic plaque burden in patients with acute coronary syndromes, as measured by intravascular ultrasound (8). More recently the same product manufactured by an improved process, called MDCO-216, was shown by us to be safe in a multiple ascending dose toxicity study in cynomolgus monkeys (9). This study also demonstrated strongly elevated free cholesterol (FC) levels and enhanced ABCA1-mediated cholesterol efflux capacity of serum after drug infusion, accompanied by a shift of apoE from HDL toward VLDL and LDL (9).…”

Section: Introductionmentioning

confidence: 99%

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Persistent changes in lipoprotein lipids after a single infusion of ascending doses of MDCO-216 (apoA-IMilano/POPC) in healthy volunteers and stable coronary artery disease patients

Kempen¹,

Gomaraschi

Simonelli

et al. 2016

Atherosclerosis

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Underappreciated Opportunities for High-Density Lipoprotein Particles in Risk Stratification and Potential Targets of Therapy

Rosenson

Davidson

et al. 2015

Cardiovasc Drugs Ther

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The inverse relationship between high-density lipoprotein cholesterol (HDL-C) concentrations and coronary heart disease risk is well established. As a result, in recent years there have been significant resources focused on identifying therapies that raise HDL-C and ultimately reduce cardiovascular events. Unfortunately, a number of trials aimed at increasing HDL-C have failed to show improved outcomes, and hence, have cast doubt on the importance of HDL-C as a therapeutic target. HDL-C, however, is only one measure of HDL. HDL levels can also been estimated by quantifying apolipoprotein A-I (apoA-I) levels using enzyme immunoassay or by measuring HDL particle number (HDL-P) using nuclear magnetic resonance spectroscopy (NMR) or ion mobility. While these surrogate measures are correlated, they are not comparable. Lipoprotein-altering therapies have been shown to have different effects on HDL-C, apoA-I and HDL-P and several studies have demonstrated that HDL-P is a stronger predictor of coronary heart disease risk than HDL-C and/or apoA-I. This paper will review available evidence supporting the use of HDL-P as the biomarker of choice to assess the contribution of HDL to cardiovascular risk and as the primary goal of HDL-raising therapies.

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Effect of repeated apoA-IMilano/POPC infusion on lipids, (apo)lipoproteins, and serum cholesterol efflux capacity in cynomolgus monkeys

Cited by 26 publications

References 61 publications

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Persistent changes in lipoprotein lipids after a single infusion of ascending doses of MDCO-216 (apoA-IMilano/POPC) in healthy volunteers and stable coronary artery disease patients

Underappreciated Opportunities for High-Density Lipoprotein Particles in Risk Stratification and Potential Targets of Therapy

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