Monoclonal antibody chP3R99 reduces subendothelial retention of atherogenic lipoproteins in Insulin-Resistant rats:Acute treatment versus long-term protection as an idiotypic vaccine for atherosclerosis

Abstract

Background: Atherosclerosis is triggered by the retention of apolipoprotein B-containing lipoproteins by proteoglycans. In addition to LDL, remnant lipoproteins have emerged as pivotal contributors to this pathology, particularly in the context of insulin resistance and diabetes. We have recently reported anti-atherogenic properties of a novel monoclonal antibody (chP3R99) that recognizes sulfated glycosaminoglycans on arterial proteoglycans. Methods and Results: Solid-phase assays demonstrated that chP3R99 effectively blocked over 50% lipoprotein binding to chondroitin sulfate and vascular extracellular matrix in vitro. The pre-perfusion of chP3R99 (passive/competitive effect) resulted in specific antibody-arterial accumulation and reduced fluorescent lipoprotein retention by ~60% in insulin resistant JCR:LA-cp rats. This (passive) reduction was dose-dependent (25 ug/mL - 250 ug/mL), effectively decreasing deposition of cholesterol associated with lipoproteins. In a five-week vaccination study in insulin resistant rats with (200 ug SC, once a week), chP3R99 reduced arterial lipoprotein retention, and was associated with the production of anti-CS antibodies (Ab3) able to accumulate in the arteries (dot-blot). Neither the intravenous inoculation of chP3R99 (4.5 mg/kg), nor the immunization with this antibody displayed adverse effects on lipid or glucose metabolism, insulin resistance, liver function, blood cell indices, or inflammation pathways in JCR:LA-cp rats. Conclusion: Both acute (passive) and long-term administration of chP3R99 antibody reduced LDL and remnant lipoprotein interaction with proteoglycans in an insulin-resistant setting. These findings support the innovative approach of targeting pro-atherogenic lipoprotein retention by this mAb as a passive therapy or as an idiotypic vaccine for atherosclerosis.