Use and role of monoclonal antibodies and other biologics in preventive cardiology

Abstract

Biotechnological advances now enable the design of fully human antibodies to target specific antigens in a growing number of diseases. Monoclonal antibodies (mAbs) differ from traditional small chemical molecules in several ways: (1) biological production ‒ they are grown in and extracted from cell cultures; (2) specificity ‒ they demonstrate high target specificity, with a low risk of drug-drug interactions; (3) administration ‒ they are delivered parenterally (intravenously or subcutaneously); (4) dosage interval ‒ their extended half-lives generally allow for spaced dosing (from weekly to monthly). In cardiology, fully human mAbs directed against proprotein convertase subtilisin / kexin type 9 (PCSK9) have shown to be effective in reducing low-density lipoprotein cholesterol (LDL-C) in phase II clinical trials among patients with familial hypercholesterolaemia (FH). PCSK9 inhibitors have just received approval for the treatment of FH and clinical atherosclerotic disease, and patients not at target under maximally tolerated statin therapy or intolerant to statins. Large-scale phase III trials are currently assessing the role of PCSK9 inhibitors in the secondary prevention setting for patients with acute coronary syndromes (ACS) and poorly controlled LDL-C under evidence-based therapies. Another area currently under investigation for fully human mAbs in secondary prevention is their potential ability to inhibit inflammatory pathways. In this context, canakinumab, a specific mAb inhibiting interleukin-1β (IL-1β), has already received approval for the treatment of systemic juvenile idiopathic arthritis. The canakinumab anti-inflammatory thrombosis outcomes trial (CANTOS) is an ongoing trial assessing whether inhibition of IL-1β could reduce the occurrence of cardiovascular adverse events in 17,200 patients with ACS and with defined persisting inflammation.

The Use of Monoclonal Antibody-Based Proprotein Convertase Subtilisin-Kexin Type 9 (PCSK9) Inhibitors in the Treatment of Hypercholesterolemia

“…PCSK9 is a ligand for LDL receptors and the identification of its function in metabolizing lipids has led to efforts for the development of novel therapies that could either reduce its levels in the body or inhibit it through protein synthesis or by binding with LDL receptors [ 21 ]. Free circulating PCSK9 results in a reduction of hepatic surface LDL receptors, causing an increase in LDL-C levels due to low clearance on account of lysosomal degradation of the receptors [ 13 ]. Unlike small therapeutic molecules, biologic therapies exhibit higher levels of target specificity and possess a lower potential for drug-to-drug interactions due to their elimination through the reticuloendothelial system.…”

“…Unlike small therapeutic molecules, biologic therapies exhibit higher levels of target specificity and possess a lower potential for drug-to-drug interactions due to their elimination through the reticuloendothelial system. About 80% of human antibodies belong to the immunoglobulin G (IgG) subtype, and all of them are naturally produced by the B cells in the human body [ 13 ].…”

“…It has also been identified that increased or decreased levels of LDL-C could be associated with gain- or loss-of-function mutations for PCSK9 [ 11 , 12 ]. Mutations of PCSK9 have been recognized as genetic markers of familial hypercholesterolemia (FH), whereas lower levels of LDL-C, as well as reduced risk of coronary heart diseases, were found in those with loss-of-function mutations [ 13 ]. A new therapeutic target for LDL-C reduction was identified upon inhibition of PCSK9 binding to LDL receptors on hepatocytes, which led to an increased density of the LDL receptors and elimination of LDL particles from the bloodstream.…”

Current and future therapies for addressing the effects of inflammation on HDL cholesterol metabolism

“…Monoclonal antibodies. A monoclonal antibody, canakinumab, is an IL-1β inhibitor which has been shown to be effective in treating juvenile RA (Gencer et al, 2015). The canakinumab anti-inflammatory thrombosis outcomes study trial is currently underway to determine the effects of canakinumab on stable CVD patients who exhibit high levels of inflammation (hsCRP >2 mg. L -1 ; Ridker et al, 2011).…”

New concepts in the management of dyslipidaemiaa

“…PCSK9 inhibitors have been intensively studied over recent years in phase III clinical studies showing dramatic decreases in LDL-C levels in patients intolerant to statins, or on top of the maximum tolerated dose of statin [14,31].…”