Combined administration of RG7652, a recombinant human monoclonal antibody against PCSK9, and atorvastatin does not result in reduction of immune function.
RG7652 is a human IgG1 monoclonal antibody designed to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) binding to hepatic low density lipoprotein receptor (LDL-r), thereby blocking PCSK9-mediated degradation of LDL-r. This therapeutic candidate is under development for the prevention of cardiovascular mortality and morbidity in dyslipidemic patients. The primary objective of this study was to evaluate the potential immunotoxicological effects of RG7652 when given to cynomolgus monkeys either alone or in combination with a daily oral dose of atorvastatin. Administration of RG7652 via subcutaneous injection every other week for 12 weeks (a total of seven doses), daily oral doses of atorvastatin (total of 85 doses), and combinations of each up to 15 and 20 mg/kg/dose, respectively, were well tolerated and there was no evidence of alteration in immune function. Administration of pharmacologically relevant doses of RG7652 in combination with atorvastatin to healthy monkeys does not result in clinically meaningful immunosuppression as measured by T-cell dependent antibody responses, natural killer cell activity, immunophenotype, or delayed type hypersensitivity. The only pharmacologically mediated changes observed during the dosing period were the anticipated changes in circulating cholesterol.
Safety Assessment, Genentech Inc., South San Francisco, 94080 California.
Thomas R
TR
Gelzleichter
Safety Assessment, Genentech Inc., South San Francisco, 94080 California.
Wendy
W
Halpern
ITGR/NTA Pharmacodynamic Biomarkers, Genentech Inc., South San Francisco, California.
Roy
R
Erwin
Charles River Laboratories, Preclinical Services, Reno, 89431 Nevada.
Amos
A
Baruch
Preclinical and Translational Pharmacokinetics, Genentech Inc., South San Francisco, California.
Maya
M
Leabman
ITGR/NTA Pharmacodynamic Biomarkers, Genentech Inc., South San Francisco, California.
Abigail S
AS
Forrest
ITGR/NTA Pharmacodynamic Biomarkers, Genentech Inc., South San Francisco, California.
Christina M
CM
Satterwhite
BioAnalytical Sciences, Genentech Inc., South San Francisco, California.
Kun
K
Peng
ITGR/NTA Pharmacodynamic Biomarkers, Genentech Inc., South San Francisco, California.
Jennifer
J
Chilton
Safety Assessment, Genentech Inc., South San Francisco, 94080 California.
Dale
D
Stevens
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents / Q000008:administration & dosage; D000069059:Atorvastatin; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage*; D006968:Hypersensitivity, Delayed; D008252:Macaca fascicularis; D008297:Male; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000276:immunology*; D011758:Pyrroles / Q000008:administration & dosage*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000276:immunology*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D011758:Pyrroles; C000600650:RG7652; D011994:Recombinant Proteins; D000069059:Atorvastatin; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
PCSK9; atorvastatin; immunotoxicology; nonhuman primate; therapeutic monoclonal antibody