title: Safety and pharmacokinetics of single intravenous dose of MGAWN1, a novel monoclonal antibody to West Nile virus.
abstract: West Nile Virus (WNV) is a neurotropic flavivirus that can cause debilitating diseases, such as encephalitis, meningitis, or flaccid paralysis. We report the safety, pharmacokinetics, and immunogenicity of a recombinant humanized monoclonal antibody (MGAWN1) targeting the E protein of WNV in a phase 1 study, the first to be performed on humans. A single intravenous infusion of saline or of MGAWN1 at escalating doses (0.3, 1, 3, 10, or 30 mg/kg of body weight) was administered to 40 healthy volunteers (30 receiving MGAWN1; 10 receiving placebo). Subjects were evaluated on days 0, 1, 3, 7, 14, 21, 28, 42, 56, 91, 120, and 180 by clinical assessments, clinical laboratory studies, electrocardiograms (ECGs), and pharmacokinetic and immunogenicity assays. All 40 subjects tolerated the infusion of the study drug, and 39 subjects completed the study. One serious adverse event of schizophrenia occurred in the 0.3-mg/kg cohort. One grade 3 neutropenia occurred in the 3-mg/kg cohort. Six MGAWN1-treated subjects experienced 11 drug-related adverse events, including diarrhea (1 subject), chest discomfort (1), oral herpes (1), rhinitis (1), neutropenia (2), leukopenia (1), dizziness (1), headache (2), and somnolence (1). In the 30-mg/kg cohort, MGAWN1 had a half-life of 26.7 days and a maximum concentration in serum (C(max)) of 953 microg/ml. This study suggests that single infusions of MGAWN1 up to 30 mg/kg appear to be safe and well tolerated in healthy subjects. The C(max) of 953 microg/ml exceeds the target level in serum estimated from hamster studies by 28-fold and should provide excess WNV neutralizing activity and penetration into the brain and cerebrospinal fluid (CSF). Further evaluation of MGAWN1 for the treatment of West Nile virus infections is warranted.
authors.affiliation: MacroGenics Inc., Rockville, MD, USA. jbeigel@niaid.nih.gov
authors.forename: John H
authors.initials: JH
authors.lastname: Beigel
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Nordstrom
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Pillemer
authors.forename: Cory
authors.initials: C
authors.lastname: Roncal
authors.forename: D Ronald
authors.initials: DR
authors.lastname: Goldwater
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: P Chris
authors.initials: PC
authors.lastname: Holland
authors.forename: Syd
authors.initials: S
authors.lastname: Johnson
authors.forename: Kathryn
authors.initials: K
authors.lastname: Stein
authors.forename: Scott
authors.initials: S
authors.lastname: Koenig
mesh_terms: D000328:Adult; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology / Q000493:pharmacokinetics*; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000276:immunology; D000914:Antibodies, Viral / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000276:immunology; D006224:Cricetinae; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000209:etiology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D014901:West Nile Fever / Q000628:therapy; D014902:West Nile virus / Q000276:immunology*; D055815:Young Adult
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D011994:Recombinant Proteins