A VLP-based vaccine targeting ANGPTL3 lowers plasma triglycerides in mice

Abstract

Elevated triglycerides (TGs) are an important risk factor for the development of coronary heart disease (CHD) and in acute pancreatitis. Angiopoietin-like proteins 3 (ANGPTL3) and 4 (ANGPTL4) are critical regulators of TG metabolism that function by inhibiting the activity of lipoprotein lipase (LPL), which is responsible for hydrolyzing triglycerides in lipoproteins into free fatty acids. Interestingly, individuals with loss-of-function mutations in ANGPTL3 and ANGPTL4 have low plasma TG levels, have a reduced risk of CHD, and are otherwise healthy. Consequently, interventions targeting ANGPTL3 and ANGPTL4 have emerged as promising new approaches for reducing elevated TGs. Here, we developed virus-like particle (VLP) based vaccines that target the LPL binding domains of ANGPTL3 and ANGPTL4. ANGPTL3 VLPs and ANGPTL4 VLPs are highly immunogenic in mice and vaccination with ANGPTL3 VLPs, but not ANGPTL4 VLPs, was associated with reduced steady state levels of TGs. Immunization with ANGPTL3 VLPs rapidly cleared circulating TG levels following an oil gavage challenge and enhanced plasma LPL activity. These data indicate that targeting ANGPTL3 by active vaccination is potential alternative to other ANGPTL3-inhibiting therapies.

Pharmacotherapy of Dyslipidemias

“…Recently, Fowler et al evaluated the effectiveness of virus-like particle (VLP)-based vaccines targeting epitopes in the LDL-R domain of PCSK9 [179]. VLP vaccine reduced LDL-C levels in combination with statins, whereas immunization with bivalent vaccine reduced LDL-C levels without requiring statin.…”

Focus on the Lymphatic Route to Optimize Drug Delivery in Cardiovascular Medicine

“…People with loss-of-function mutations in ANGPTL3-encoding genes exhibit reduced TG level and a low risk of CVD. Thus, vaccination against ANGPTL3 could serve as a promising strategy for protection against hypertriglyceridemia and relative CVD [ 158 ].…”

ANGPTL4: a new mode in the regulation of intravascular lipolysis

“…This relationship is clearly illustrated by the lethal intestinal phenotype with lymphatic nodule inflammation that develops when whole body Angptl4 −/− mice or wt mice treated with an ANGPTL4-neutralizing antibody are fed a high fat diet that is rich in saturated fatty acids [17–19]. The interest in systemic targeting of ANGPTL4 with neutralizing monoclonal antibodies as a therapeutic agent for lipid lowering therefore waned and the focus shifted towards targeting hepatic ANGPTL4 expression using N-acetylgalactosamine-conjugated antisense oligonucleotides (ASO) [16 ▪ ], but the primary effort is nevertheless still devoted to systemic inhibition of ANGPTL3 with neutralizing antibodies and ASOs [20,21 ▪ ,22,23]. Figure 1 shows a schematic illustration of LPL regulation and compartmentalization in the intravascular unit, which comprises the capillary endothelial cells, the subendothelial space, rich in heparasulfate proteoglycans (HSPGs), and the parenchymal cells synthesizing LPL (adipocytes or myocytes)…”