title: Immunogenicity, Inflammation, and Lipid Accumulation in Cynomolgus Monkeys Infused with a Lipidated Tetranectin-ApoA-I Fusion Protein.
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 monocytes/macrophages in multiple organs, which in the glomeruli were shown to be CD68-positive, contain lipid and co-localized with granular IgG deposits. Lipid accumulation may have been a direct result of a high drug load, possibly enhanced by immune complex formation, inflammation, and altered lipid metabolism. Noteworthy was the inter- individual inconsistency in the severity of clinical and histopathologic findings, drug clearance and inflammatory markers. In conclusion, multiple infusions of lipidated TN-ApoA-I resulted in high immunogenicity, lipid accumulation and were not well tolerated in nonhuman primates.
authors.affiliation: *Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel 4070, Switzerland; franziska.regenass@roche.com.
authors.forename: Franziska
authors.initials: F
authors.lastname: Regenass-Lechner
authors.affiliation: Roche Pharmaceutical Research and Early Development, Bioanalytical Research and Development, Roche Innovation Center Penzberg, Roche Diagnostics GmbH, Penzberg 82377, Germany;
authors.forename: Roland F
authors.initials: RF
authors.lastname: Staack
authors.affiliation: *Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel 4070, Switzerland;
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Mary
authors.affiliation: *Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel 4070, Switzerland;
authors.forename: Wolfgang F
authors.initials: WF
authors.lastname: Richter
authors.affiliation: *Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel 4070, Switzerland;
authors.forename: Michael
authors.initials: M
authors.lastname: Winter
authors.affiliation: Roche Pharmaceutical Research and Early Development, Bioanalytical Research and Development, Roche Innovation Center Penzberg, Roche Diagnostics GmbH, Penzberg 82377, Germany;
authors.forename: Gregor
authors.initials: G
authors.lastname: Jordan
authors.affiliation: *Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel 4070, Switzerland;
authors.forename: Nicole
authors.initials: N
authors.lastname: Justies
authors.affiliation: *Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel 4070, Switzerland;
authors.forename: Anja
authors.initials: A
authors.lastname: Langenkamp
authors.affiliation: Former Department of Nonclinical Safety, Hoffmann-La Roche Inc, Nutley, New Jersey 07110; and.
authors.forename: Rosario
authors.initials: R
authors.lastname: Garrido
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center New York, F. Hoffmann-La Roche Ltd, New York, New York 10016.
authors.forename: Mudher
authors.initials: M
authors.lastname: Albassam
authors.affiliation: *Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel 4070, Switzerland;
authors.forename: Thomas
authors.initials: T
authors.lastname: Singer
authors.affiliation: *Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel 4070, Switzerland;
authors.forename: Elke-Astrid
authors.initials: EA
authors.lastname: Atzpodien
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000097:blood*; D016632:Apolipoprotein A-I / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics / Q000633:toxicity*; D002097:C-Reactive Protein / Q000032:analysis; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D005340:Fibrinogen / Q000032:analysis; D007249:Inflammation / Q000097:blood / Q000139:chemically induced; D007262:Infusions, Intravenous; D037181:Lectins, C-Type / Q000008:administration & dosage* / Q000276:immunology; D008055:Lipids / Q000097:blood* / Q000276:immunology; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics / Q000633:toxicity*
chemical_list: D000936:Antigen-Antibody Complex; D016632:Apolipoprotein A-I; D016207:Cytokines; D005338:Fibrin Fibrinogen Degradation Products; D037181:Lectins, C-Type; D008055:Lipids; D011993:Recombinant Fusion Proteins; C036309:fibrin fragment D; C048648:tetranectin; D005340:Fibrinogen; D002097:C-Reactive Protein
keywords: cytokines; histopathology; immunotoxicity; inflammation; toxicokinetics.