Lipid-Lowering Biotechnological Drugs: from Monoclonal Antibodies to Antisense Therapies—a Clinical Perspective

2020 ◽  
Author(s):  
Xiaoming Jia ◽  
Jing Liu ◽  
Anurag Mehta ◽  
Christie M. Ballantyne ◽  
Salim S. Virani
Keyword(s):  
Monoclonal Antibodies ◽  
Lipid Lowering ◽  
Clinical Perspective ◽  
Biotechnological Drugs

scholarly journals Development of Novel DNA-Encoded PCSK9 Monoclonal Antibodies as Lipid-Lowering Therapeutics

2019 ◽  
Vol 27 (1) ◽  
pp. 188-199 ◽  
Author(s):  
Makan Khoshnejad ◽  
Ami Patel ◽  
Krzysztof Wojtak ◽  
Sagar B. Kudchodkar ◽  
Laurent Humeau ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Lipid Lowering

scholarly journals Monoclonal Antibodies in the Management of Familial Hypercholesterolemia: Focus on PCSK9 and ANGPTL3 Inhibitors

2021 ◽  
Vol 23 (12) ◽  
Author(s):  
Angela Pirillo ◽  
Alberico L. Catapano ◽  
Giuseppe D. Norata
Keyword(s):  
Monoclonal Antibodies ◽  
High Risk ◽  
Familial Hypercholesterolemia ◽  
Plasma Levels ◽  
Low Density Lipoprotein ◽  
Genetic Defect ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Low Density ◽  
Premature Cardiovascular Disease

Abstract Purpose of Review Familial hypercholesterolemia (FH) is a monogenic disorder characterized by high plasma levels of low-density lipoprotein cholesterol (LDL-C) since birth and a high risk of premature cardiovascular disease. The genetic defect is carried in only one allele in heterozygous FH (HeFH) or in both in the most severe homozygous FH (HoFH). Current guidelines recommend to reduce substantially LDL-C levels in these high-risk patients, with the need to use association therapy combining agents with different mechanisms of action. As most cases of FH are attributable to mutations in the gene encoding the low-density lipoprotein receptor (LDLR), statins, even in combination with ezetimibe, are less effective in reducing LDL-C plasma levels in FH patients, who require a more intensive approach with additional lipid-lowering agents. Additional targets playing key roles in regulating LDL-C levels are represented by PCSK9 and ANGPTL3. Recent Findings Two monoclonal antibodies (mAbs) targeting PCSK9, evolocumab and alirocumab, significantly reduce LDL-C levels in HeFH patients. In patients with HoFH, the efficacy of mAbs to PCSK9 is strictly related to the presence of a residual LDLR activity; thus, patients carrying null mutations do not respond to the therapy with these mAbs, whereas some effects can be appreciated in HoFH bearing defective mutations. Conversely, evinacumab, the mAb targeting ANGPTL3, is highly effective in reducing LDL-C levels even in HoFH patients carrying null LDLR mutations, thanks to its LDLR-independent mechanism of action. Summary Monoclonal antibodies inhibiting PCSK9 have shown a robust effect in FH patients presenting a residual LDLR activity, while ANGPTL3 inhibitors appear to be promising even in patients carrying null LDLR mutations.

Lipid-Lowering Therapies for Atherosclerosis: Statins, Fibrates, Ezetimibe and PCSK9 monoclonal antibodies

2021 ◽  
Vol 28 ◽  
Author(s):  
Adel Hajj Ali ◽  
Nour Younis ◽  
Rola Abdallah ◽  
Farah Shaer ◽  
Ali Dakroub ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Lipid Metabolism ◽  
Plasma Cholesterol ◽  
Therapeutic Interventions ◽  
Lipid Lowering ◽  
Lipid Metabolism Disorder ◽  
Metabolism Disorder ◽  
Peripheral Arterial Diseases ◽  
Branching Points ◽  
Genetic Interventions

: Cardiovascular disease (CVD) remains the primary cause of global morbidity and mortality. CVD includes various life-threatening conditions such as myocardial infarction, stroke and peripheral arterial diseases. In this context, atherosclerosis continues to play the principal role in the pathogenesis of these conditions. Atherosclerosis emanates from a set of modifiable and non-modifiable risk factors that include age, male gender, family history, obesity, smoking, diabetes mellitus and hypertension. Recent evidence classifies atherosclerosis as a latent disease affecting all-sized arteries with a predilection for arterial branching points of decreased or absent blood supply. Atherosclerosis is not only a lipid metabolism disorder, but is also a chronic inflammatory one. In this review, we provide a synoptic discussion of the underlying pathological mechanisms of atherosclerosis along with the currently applied therapeutic interventions. We then discuss the classical lipid-lowering therapies as well as the newly discovered therapies. For the classical therapies, we point out the importance of statins and ezetimibe in reducing plasma cholesterol levels by virtue of their effects on synthesis, reuptake and intestinal absorption of cholesterol. We also discuss the role of fibrates in modulating lipid metabolism and improving the ratio of high-density to low-density density lipoproteins. We then focus on the more recent molecular and genetic interventions exemplified by proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies, evinacumab, and microRNA inhibitors. Special attention is also given to clinical trials involving these therapies.

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors, Reality or Dream in Managing Patients with Cardiovascular Disease

2019 ◽  
Vol 20 (1) ◽  
pp. 72-82 ◽  
Author(s):  
Mohammad Alkhalil
Keyword(s):  
Cardiovascular Disease ◽  
Monoclonal Antibodies ◽  
Cardiovascular Events ◽  
Cost Effective ◽  
Lipid Lowering ◽  
High Dose ◽  
Atherosclerotic Cardiovascular Disease ◽  
Pcsk9 Inhibitors ◽  
Ldl Receptors ◽  
Coa Reductase

Background: Statins have been a major keystone in the management of patients with atherosclerotic cardiovascular disease. The benefits of inhibiting HMG CoA reductase, via statins, were translated into reduction in LDL-c with proportionate decrease in cardiovascular events in response to the magnitude of LDL-c reduction. Despite major advances in pharmacological treatments, including the use of high-dose statins, there are urgent need to further reduce future cardiovascular risk. This is in particularly important since 1 out of 5 high-risk atherosclerotic patients who achieve low LDL-c return with a second cardiovascular event within five years. Although this residual risk post-statin is largely heterogeneous, lowering LDL-c beyond ‘normal’ or guidelines-recommended level using novel therapies has resulted in further reduction in cardiovascular events. </P><P> Objective: The current review will discuss the use of PCSK9 inhibitors in patients with atherosclerotic disease. PCSK9 inhibitors are a new class of lipid-lowering drugs that are either fully human monoclonal antibodies (evolocumab and alirocumab) or humanised monoclonal antibodies (bococizumab) that effectively reduce LDL-c to unprecedented level. By blocking circulating PCSK9, these drugs would preserve LDL receptors and prevent them from cellular degradation. This process promotes recycling of LDL receptors back to hepatocytes surface, leading into further reduction of LDL-c. Combining PCSK9 inhibitors with statin have led into lower LDL-c, reduction in plaque volume and more importantly reduction in future cardiovascular events. Conclusion: These drugs are very promising, nonetheless, the unselective approach of applying these monoclonal antibodies may not prove to be cost-effective and potentially exposing some patients to unnecessary side effects.

scholarly journals The Use of Biotechnological Drugs in Pediatrics on the Example of Monoclonal Antibodies: Clinical Pharmacology View

2021 ◽  
Vol 18 (4) ◽  
pp. 304-313
Author(s):  
Alexey S. Kolbin ◽  
Liudmila I. Yemelyanova
Keyword(s):  
Monoclonal Antibodies ◽  
Adverse Effects ◽  
Growth And Development ◽  
Drug Selection ◽  
Moving Targets ◽  
Physiological Processes ◽  
Age Related ◽  
Adults And Children ◽  
Biotechnological Drugs

The article reviews monoclonal antibodies, its structure, classifications, pharmacodynamics, pharmacokinetics, and adverse effects. There are examples for each section. Approaches to the research and criteria for drug selection in paediatrics are discussed in detail: the role of clinical trials, extrapolation and pharmacometrics. It has been shown that the differences in the pharmacokinetics of monoclonal antibodies between adults and children present due to the age-related characteristics of various physiological processes. The authors analyse such parameters as absorption, bioavailability, distribution, and elimination. The role of monoclonal antibodies immunogenicity in the structure of adverse effects in children is fully presented. Pharmacometrics is reviewed in the form of modelling and simulation in monoclonal antibodies dosing in paediatrics. It is important to consider the growth and development as “moving targets" in pediatrics regardless the principle of monoclonal antibodies dosage in children. The conclusions were made, and the guidelines were prepared based on the article results.

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