title: Anti-IL21 receptor monoclonal antibody (ATR-107): Safety, pharmacokinetics, and pharmacodynamic evaluation in healthy volunteers: a phase I, first-in-human study.
abstract: Safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ATR-107, a fully human monoclonal anti-IL-21 receptor (IL-21R) antibody, administered as ascending single doses, subcutaneously or intravenously, was evaluated in a placebo-controlled, double-blind trial in healthy subjects. The dose levels were 3-300 mg by SC and 30-120 mg by IV. The most important adverse events were hypersensitivity reactions occurring in three out of six subjects in 300 mg SC cohort and considered as dose limiting toxicity. More than 75% of the subjects who received ATR-107 developed anti-drug antibodies (ADAs), which had no discernible impact on PK or safety. The PK of ATR-107 appeared to be dose -proportional. T1/2 was shorter than typical therapeutic antibodies. Bioavailability of ATR-107 was about 30%. IL-21R occupancy was measured in circulating B cells in the 60 and 120 mg IV cohort. The data indicated that single dose of ATR-107 was able to maximally occupy IL-21Rs through at least Day 42. Further escalation in the FIH study was halted partially due to the high rates of ADA formation. In conclusion, ATR-107 had a prolonged PD effect measured by IL-21R occupancy; was highly immunogenic after single dose administration and had PK properties with rapid clearance and low bioavailability.
authors.affiliation: Department of Quantitative Clinical Sciences, BioTx Clinical Research and Development, Pfizer, Inc., Cambridge, MA, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Hua
authors.forename: Gail M
authors.initials: GM
authors.lastname: Comer
authors.forename: Lori
authors.initials: L
authors.lastname: Stockert
authors.forename: Bo
authors.initials: B
authors.lastname: Jin
authors.forename: John
authors.initials: J
authors.lastname: Nowak
authors.forename: Susan
authors.initials: S
authors.lastname: Pleasic-Williams
authors.forename: David
authors.initials: D
authors.lastname: Wunderlich
authors.forename: John
authors.initials: J
authors.lastname: Cheng
authors.forename: Jean S
authors.initials: JS
authors.lastname: Beebe
mesh_terms: D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001682:Biological Availability; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D053655:Receptors, Interleukin-21 / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: C000591157:ATR-107; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053655:Receptors, Interleukin-21
keywords: IL-21; anti-drug antibody; first in human; hypersensitivity; immunogenicity; pharmacodynamics; pharmacokinetics; receptor occupancy