Immunogenicity, Inflammation, and Lipid Accumulation in Cynomolgus Monkeys Infused with a Lipidated Tetranectin-ApoA-I Fusion Protein

Toxicological Sciences : an Official Journal of the Society of Toxicology
Franziska Regenass-LechnerElke-Astrid Atzpodien

Abstract

High density lipoprotein (HDL)-targeted therapies, which promote cholesterol efflux from cells, are currently in development for reducing cardiovascular events in acute coronary syndrome. Human apolipoprotein A-I (apoA-I), the major HDL protein, was fused to the trimerization domain of tetranectin (TN) and complexed with phospholipids to generate a HDL mimetic (lipidated TN-ApoA-I) with reduced renal clearance and enhanced efficacy. Cynomolgus monkeys received 24-h intravenous infusions of control, 100 mg/kg or 400 mg/kg lipidated TN-ApoA-I every 4 days for 3 weeks, followed by a 6-week recovery period. After multiple infusions of lipidated TN-ApoA-I, clinical condition deteriorated and was accompanied by changes indicative of a progressive inflammatory response; increased levels of cytokines, C-reactive protein and vascular/perivascular infiltrates in multiple tissues. Rapid formation of antidrug antibodies occurred in all animals receiving lipidated TN-ApoA-I. Enhanced drug clearance corresponding to a relative lack of high molecular weight immune complexes in blood, suggestive of preferred removal/clearance, was observed in some animals. Expected dose-dependent increases in serum lipids were accompanied by vacuolated monocyt...Continue Reading

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Citations

Oct 26, 2018·Regulatory Toxicology and Pharmacology : RTP·Mohammed BourdiPramod S Terse

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