Abstract 29: PCSK9 Association With Lipoprotein(a)

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Hagai Tavori ◽  
Ilaria Giunzioni ◽  
Calvin Yeang ◽  
Sotirios Tsimikas ◽  
Michael D Shapiro ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Monoclonal Antibodies ◽  
Immune Complexes ◽  
Ldl Cholesterol ◽  
Sandwich Elisa ◽  
Mononuclear Phagocyte ◽  
Lower Plasma ◽  
Ldl Receptors ◽  
Lipoprotein A ◽  
Cholesterol Levels

Monoclonal antibodies (mAb) against PCSK9 lower plasma LDL-cholesterol levels by increasing the lifespan of LDL receptors (LDLR). Significant effects on lipoprotein(a) [Lp(a)] have also been observed, but the mechanism for this is neither known nor intuitive since Lp(a) is not cleared by LDLR. Our and other laboratories have shown that PCSK9 associates with LDL in plasma. Here, we aimed to study whether PCSK9 also associates with Lp(a) particles and whether this association depends on Lp(a) levels and/or apo(a) size. Using sandwich ELISA we determined that plasma PCSK9 is indeed associated with Lp(a) particles in patient with high Lp(a) levels (>30mg/dl). We then isolated LDL and Lp(a) fractions from plasma of 8 patients with high Lp(a) levels, ranging from 36 to 224 mg/dl, and determined PCSK9 and apoB levels as well as apo(a) isoforms. Our results show a 17.8 fold higher PCSK9/apoB ratio for Lp(a) compared with LDL (Fig. 1A), which suggests a preferential distribution of PCSK9 with Lp(a), at least in high Lp(a) individuals. Surprisingly, the preferential association of PCSK9 with Lp(a) was inversely correlated to Lp(a) levels (Fig. 1B) and independent of LDL levels. Since Lp(a) levels are inversely correlated with the size of apo(a), we set out to determine whether PCSK9 association with Lp(a) is related to the molecular weight of apo(a). Using plasma of patients with two distinct apo(a) isoforms, we show that PCSK9 associates exclusively with the higher molecular weight of apo(a) (Fig. 1C). Our results suggest that Lp(a)-bound PCSK9 exists in plasma of patients with high Lp(a) and that this association depends on the size of apo(a). This provides a possible mechanism for the reduction in Lp(a) caused by PCSK9mAb, as immune complexes mAb-PCSK9-Lp(a) may be cleared via the mononuclear phagocyte system.

scholarly journals Monoclonal Antibodies Recognising Sialyl-Tn: Production and Application to Immunochemistry

1994 ◽  
Vol 12 (3) ◽  
pp. 175-186 ◽  
Author(s):  
Peter L. Devine ◽  
Geoffrey W. Birrell ◽  
Rachel J. Quin ◽  
Paul W. Shield
Keyword(s):  
Molecular Weight ◽  
Monoclonal Antibodies ◽  
Normal Tissue ◽  
Sandwich Elisa ◽  
Ovarian Tumour ◽  
Tn Antigen ◽  
Bovine Submaxillary Mucin ◽  
Sialyl Tn Antigen ◽  
Ovine Submaxillary Mucin ◽  
Sialyl Tn

In order to develop reagents that can detect the exposed sialyl-Tn antigen (NeuAcα2,6GaINAcα 1-O-Ser/Thr) on tumour-associated mucins, we have prepared monoclonal antibodies (mabs 3C2 and 301, both IgM) against ovine submaxillary mucin (OSM; >98% of glycans as sialyl-Tn). These mabs showed strong reactivity with OSM and bovine submaxillary mucin (BSM; 50% of glycans as sialyl-Tn) but did not react with desialylated OSM or BSM. Sialic acid at I mg/ml did not significantly inhibit mab binding to OSM, suggesting that the linkage to GalNAc may be important for mab binding. 3C2 and 3D I also showed similar reactivity to sialyl-Tn reactive mab Bn.3, and detected Bn.3 capturedOSM in a sandwich ELISA. In Western blotting of mucus from a patient with a mucinous ovarian tumour, the mabs reacted with high molecular weight (>200 kDa) species. In immunohistochemistry, these mabs showed strong reactivity with most cancers of the colon, lung, and stomach, and also some tumours of the ovary and breast. There was only limited reactivity in normal tissue from these sites. The antibodies should be useful reagents for the detection of the sialyl-Tn antigen in human cancers.

scholarly journals Korszerű lipidcsökkentő kezelés

2016 ◽  
Vol 157 (31) ◽  
pp. 1219-1223 ◽  
Author(s):  
György Paragh ◽  
István Karádi
Keyword(s):  
Monoclonal Antibodies ◽  
Cardiovascular Events ◽  
Ldl Cholesterol ◽  
Cholesterol Absorption ◽  
New Agents ◽  
Considerable Evidence ◽  
Cholesterol Levels ◽  
Cholesterol Absorption Inhibitor ◽  
Reasonable Approach ◽  
New Strategies

Considerable evidence suggests that “the lower the better” is a reasonable approach for reducing cardiovascular risk by lowering LDL cholesterol levels. Despite the reduction in cardiovascular events and mortality achieved by statin therapy, significant residual risk remains, especially in severe hereditary hypercholesterolemia, such as familial hypercholesterolemia. Some new strategies to achieve even lower LDL levels are now available, including the addition of cholesterol absorption inhibitor ezetimibe, and the recently available Proprotein convertase subtilisin/kexin type 9 monoclonal antibodies. In addition, new LDL drugs may be effectively administrated in those individuals who are unable to tolerate statins. The authors summarize the efficacy and clinical indications of these new agents and review the currently available guidelines. Orv. Hetil., 2016, 157(31), 1219–1223.

Abstract P192: Lipoprotein(a) is Significantly Associated with ApoB-containing Atherogenic Lipoproteins in African Americans

Circulation ◽  
2012 ◽  
Vol 125 (suppl_10) ◽  
Author(s):  
Enkhmaa Byambaa ◽  
Anuurad Erdembileg ◽  
Wei Zhang ◽  
Lars Berglund
Keyword(s):  
African Americans ◽  
Total Cholesterol ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Sandwich Elisa ◽  
Plasma Lipid ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Lipoprotein A ◽  
Interethnic Difference

Background: Lipoprotein(a), Lp(a), is a genetically regulated independent cardiovascular risk factor, where levels differ across ethnicity. The relationship between Lp(a) and apolipoprotein B (apoB)-containing atherogenic lipoproteins across ethnicity is not well understood. Objective: To investigate the associations of Lp(a) levels with other apoB-containing lipoproteins with a focus on ethnicity. Methods: Plasma lipid and lipoproteins were measured in 336 Caucasians and 224 African Americans undergoing coronary angiography. Lp(a) levels were determined using an apo(a) size insensitive sandwich ELISA. Values for Lp(a) and triglyceride (TG) were square root or logarithmically transformed before analyses. Total and low density lipoprotein (LDL) cholesterol, and apoB levels were corrected for contribution of Lp(a) using previously published algorithms. Values are given mean ± standard deviation or median (interquartile range) for normally or non-normally distributed variables, respectively. Results: Levels of total and LDL cholesterol and apoB-100 did not differ between Caucasians and African Americans. As expected, African Americans had significantly higher levels of Lp(a) [110 (60-180) nmol/l vs. 24 (7-79) nmol/l, p<0.001] and high density lipoprotein (HDL) cholesterol (49±17 mg/dl vs. 41±12 mg/dl, p<0.001), as well as significantly lower levels of TG [106 (80-144) mg/dl vs. 153 (114-222) mg/dl, p<0.001] compared to Caucasians. For both ethnic groups, Lp(a) levels were significantly and positively correlated with total cholesterol (p<0.005 for Caucasians and p<0.001 for African Americans), LDL cholesterol (p<0.001 for both groups), apoB100 (p<0.05 for Caucasians and p<0.001 for African Americans) and apoB/apoA-1 ratio (p<0.05 for Caucasians and p<0.001 for African Americans). However, when adjusted for the corresponding contribution of Lp(a) to the levels of these parameters, the associations remained significant in African Americans (p<0.05 for total cholesterol; p<0.05 for LDL cholesterol; p<0.001 for apoB100, respectively), but not in Caucasians. Conclusion: Although total and LDL cholesterol, and apoB100 levels were comparable in African Americans and Caucasians, the associations of these parameters with Lp(a) levels differed across ethnicity. For African Americans, but not for Caucasians, associations of all three parameters with Lp(a) remained significant after appropriate adjustments. The findings suggest an interethnic difference in the relation between Lp(a) and other plasma apoB-containing lipoprotein levels, with a closer relationship among African Americans.

Comparative study of assays detecting circulating immune complexes and specific antibodies in patients infected with Toxocara canis

1987 ◽  
Vol 61 (3) ◽  
pp. 196-202 ◽  
Author(s):  
C. Aguila ◽  
C. Cuéllar ◽  
S. Fenoy ◽  
J. L. Guillén
Keyword(s):  
Monoclonal Antibodies ◽  
Comparative Study ◽  
Immune Complexes ◽  
Sandwich Elisa ◽  
Toxocara Canis ◽  
Circulating Immune Complexes ◽  
Soluble Antigen ◽  
Elisa Method ◽  
Active Infection ◽  
Specific Antibodies

ABSTRACTA sandwich ELISA method using previously described E/S antigen-specific monoclonal antibodies has been developed to detect circulating immune complexes in patients infected with Toxocara canis. This technique could be used for the study of the dynamics of the parasite-host relationship, as we believe the detection of immune complexes and/or soluble antigen to be an improvement over detection of antibodies only. In this parasitosis, antibodies may be present in residual levels for prolonged periods after active infection.

Niacin as antidyslipidemic drug

2015 ◽  
Vol 93 (12) ◽  
pp. 1043-1054 ◽  
Author(s):  
Ulrich Julius
Keyword(s):  
Ldl Cholesterol ◽  
Hdl Cholesterol ◽  
Vitamin B3 ◽  
End Points ◽  
Lipoprotein A ◽  
Beneficial Effects ◽  
Lipid Disorders ◽  
Cholesterol Levels ◽  
Low Hdl ◽  
Review Reports

Niacin is an important vitamin (B3) that can be used in gram doses to positively modify pathogenetically relevant lipid disorders: elevated LDL cholesterol, elevated non-HDL cholesterol, elevated triglycerides, elevated lipoprotein(a), and reduced HDL cholesterol. This review reports the latest published findings with respect to niacin’s mechanisms of action on these lipids and its anti-inflammatory and anti-atherosclerotic effects. In the pre-statin era, niacin was shown to have beneficial effects on cardiovascular end-points; but in recent years, two major studies performed in patients whose LDL cholesterol levels had been optimized by a statin therapy did not demonstrate an additional significant effect on these end-points in the groups where niacin was administered. Both studies have several drawbacks that suggest that they are not representative for other patients. Thus, niacin still plays a role either as an additive to a statin or as a substitute for a statin in statin-intolerant patients. Moreover, patients with elevated triglyceride and low HDL cholesterol levels and patients with elevated lipoprotein(a) concentrations will possibly benefit from niacin, although currently the study evidence for these indications is rather poor. Niacin may be useful for compliant patients, however possible side effects (flushing, liver damage) and contraindications should be taken into consideration.

A sandwich ELISA based on anti-apo(a) and anti-apo B monoclonal antibodies for lipoprotein(a) measurement

1995 ◽  
Vol 236 (1) ◽  
pp. 59-70 ◽  
Author(s):  
Luis Sorell ◽  
Gertrudis Rojas ◽  
Miladys Rodríguez ◽  
Carlos Ramos ◽  
Lázaro Torres ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Sandwich Elisa ◽  
Apo B ◽  
Lipoprotein A

2980The effect of monoclonal antibodies against PCSK9 on circulating CD34+ progenitor cells interactions with platelets in patients with familial hypercholesterolemia

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A N Tsouka ◽  
E N Liberopoulos ◽  
C V Rizos ◽  
E C Christopoulou ◽  
M S Elisaf ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Progenitor Cells ◽  
Ldl Cholesterol ◽  
Density Lipoprotein ◽  
Cell Types ◽  
Membrane Expression ◽  
Cholesterol Levels ◽  
Cd34 Cells ◽  
Endothelial Phenotype

Abstract Introduction Platelets interact with circulating CD34+ progenitor cells inducing their differentiation into endothelial progenitor cells (EPCs) and further promoting EPC maturation into endothelial cells, an important step for endothelial regeneration and angiogenesis. PSCK9 is a serine protease that may not only play a crucial role in binding to the low density lipoprotein receptor (LDL-R) increasing its endosomal and lysosomal degradation thus inhibiting its recycling to the cell surface, leading to increasing LDL-cholesterol levels in plasma, but may also exhibit several, independent on LDL-R, activities on a plethora of cell types, including platelets. Purpose We investigated whether monoclonal antibodies (mabs) against PCSK9 could affect platelet interaction with CD34+ cells as well as their differentiation into EPCs, in patients with Familial Hypercholestorelemia (FH). Patients and methods Patients with FH (n=11, 8 men and 3 women, mean age 53±10 years) being under statin/ezetimibe therapy (40mg statin/ 10mg ezetimibe) participated in the study. Patients exhibited resisting high LDL-cholesterol levels, therefore following the existing guidelines, they received mab against PCSK9 (7 evolocumab, 140mg/ml and 4 alirocumab, 150mg/ml) every two weeks. Blood samples were drawn before and after 4 doses of the antibody i.e. after two months (Follow-up). In addition to the patients' serum lipid profile, the endothelial phenotype of CD34+ (membrane expression levels of KDR which is a receptor for VEGF and an endothelial phenotype marker) on CD34+ cells (CD34+-KDR+ cells) and the formation of platelet-CD34+ (CD61+-CD34+) and platelet-KDR+ (CD61+-KDR+) conjugates were also determined by flow cytometry on whole blood after dual labelling with anti-VEGFR-R2/KDR-PE, anti-CD61-PerCP and anti-CD34-FITC. The results were expressed as the %gated of CD34+-KDR+ cells, as well as CD61+-CD34+ and CD61+-KDR+ conjugates. Results The baseline LDL-cholesterol levels were significantly reduced from 172±43 mg/dl to 51±17 at follow-up, p=0.0001. Importantly, the formation of CD61+-CD34+ and CD61+-KDR+ conjugates were increased from baseline to follow-up (from 1.39±1.3 to 2.23±2.8, p=0.037) and (from 2.91±4.2 to 5.92±6.01, p=0.014), respectively. The membrane expression of KDR on CD34+ cells was also increased from 0.79±0.9 to 1.36±0.90, p=0.042, which reflects the increase in the CD34+ endothelial phenotype. Conclusion We show for the first time that the mabs against PCSK9, significantly increase the CD34+ endothelial phenotype in FH patients, which may at least partially attributed to the increase in the platelet interaction with CD34+ cells (platelet-CD34+ conjugates). The underlying mechanisms as well as the consequences of this effect at the clinical level for these patients are under investigation.

scholarly journals Management of Severe Dyslipidaemia: Role of PCSK9 Inhibitors

2018 ◽  
Vol 13 (1) ◽  
pp. 9 ◽  
Author(s):  
Stephen J Nicholls ◽  
Keyword(s):  
Cardiovascular Risk ◽  
Ldl Cholesterol ◽  
Pcsk9 Inhibitors ◽  
Ldl Receptors ◽  
Cholesterol Levels ◽  
Ldl Particles ◽  
Effective Removal ◽  
Biochemical Studies ◽  
Event Rates

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in regulation of LDL receptors on the hepatocyte surface and therefore is essential for effective removal of LDL particles from circulation. Genetic and biochemical studies have established that altered PCSK9 functionality influences both LDL cholesterol levels and cardiovascular risk. This has prompted development of inhibitory strategies targeting PCSK9. Study of monoclonal PCSK9 antibodies has progressed to the clinic, where they have been found to lower LDL cholesterol levels and reduce cardiovascular event rates in large, clinical outcome trials. The use of PCSK9 inhibitors in the setting of dyslipidaemia is reviewed.

scholarly journals The complexity of lipoprotein (a) lowering by PCSK9 monoclonal antibodies

2017 ◽  
Vol 131 (4) ◽  
pp. 261-268 ◽  
Author(s):  
Gilles Lambert ◽  
Aurélie Thedrez ◽  
Mikaël Croyal ◽  
Stéphane Ramin-Mangata ◽  
David Couret ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Ldl Cholesterol ◽  
Scientific Literature ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Lipoprotein A ◽  
Pcsk9 Inhibition

Since 2012, clinical trials dedicated to proprotein convertase subtilisin kexin type 9 (PCSK9) inhibition with monoclonal antibodies (mAbs) have unambiguously demonstrated robust reductions not only in low-density lipoprotein (LDL) cholesterol (LDL-C) but also in lipoprotein (a) [Lp(a)] levels. The scientific literature published prior to those studies did not provide any evidence for a link between PCSK9 and Lp(a) metabolism. More recent investigations, either in vitro or in vivo, have attempted to unravel the mechanism(s) by which PCSK9 mAbs reduce circulating Lp(a) levels, with some showing a specific implication of the LDL receptor (LDLR) in Lp(a) clearance whereas others found no significant role for the LDLR in that process. This elusive pathway appears clearly distinct from that of the widely prescribed statins that also enhance LDLR function but do not lower circulating Lp (a) levels in humans. So how does PCSK9 inhibition with mAbs reduce Lp(a)? This still remains to be established.

scholarly journals Lime-treated maize husks lower plasma LDL-cholesterol levels in normal and hypercholesterolaemic adult men from northern Mexico

1999 ◽  
Vol 81 (4) ◽  
pp. 281-288 ◽  
Author(s):  
Reyna Luz Vidal-Quintanar ◽  
Reyna Luz Mendívil ◽  
Mireya Peña ◽  
Maria Luz Fernandez
Keyword(s):  
Ldl Cholesterol ◽  
Dietary Habits ◽  
Cholesterol Metabolism ◽  
Plasma Cholesterol ◽  
Total Cholesterol Level ◽  
Hdl Cholesterol ◽  
Normal Subjects ◽  
Lower Plasma ◽  
North West ◽  
Cholesterol Levels

Lime-treated maize husks (LTCH), a by-product of tortilla manufacturing in Mexico, have been shown to decrease plasma LDL-cholesterol levels in guinea-pigs by specific alterations in hepatic cholesterol metabolism. To determine whether LTCH would also lower plasma cholesterol levels in normal and hyperlipidaemic individuals, the fibre content of a typical diet was increased by supplementing free-living subjects in North-West Mexico with cookies containing 450 g LTCH/kg. Normal subjects (n11) with plasma cholesterol levels of less than 5·7 mmol/l and hypercholesterolaemic subjects (n12) with plasma cholesterol levels higher than 5·7 mmol/l participated in the study. Plasma glucose, cholesterol, triacylglycerol, LDL-cholesterol and HDL-cholesterol concentrations, LDL: HDL values and blood pressure were determined at baseline and after 6 weeks of supplementation with LTCH. LTCH supplementation significantly lowered the plasma total cholesterol level by 11–15 % and LDL-cholesterol by 25 %, and improved the LDL: HDL value by 29–33 % (P< 0·01) in both normal and hypercholesterolaemic subjects. HDL-cholesterol, triacylglycerol and glucose concentrations did not change. Both groups consumed equal amounts of LTCH per week; individuals showed excellent compliance and good acceptance of the product. Neither group changed their dietary habits during the time of the experiment as determined by 3 d dietary records at baseline and at week 6. We conclude that LTCH supplements are suitable to increase fibre intake and reduce plasma LDL-cholesterol levels in healthy and hypercholesterolaemic subjects in this population.

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