title: Preclinical pharmacokinetics of MHAA4549A, a human monoclonal antibody to influenza A virus, and the prediction of its efficacious clinical dose for the treatment of patients hospitalized with influenza A.
abstract: MHAA4549A is a human immunoglobulin G1 (IgG1) monoclonal antibody that binds to a highly conserved epitope on the stalk of influenza A hemagglutinin and blocks the hemagglutinin-mediated membrane fusion in the endosome, neutralizing all known human influenza A strains. Pharmacokinetics (PK) of MHAA4549A and its related antibodies were determined in DBA/2J and Balb-c mice at 5 mg/kg and in cynomolgus monkeys at 5 and 100 mg/kg as a single intravenous dose. Serum samples were analyzed for antibody concentrations using an ELISA and the PK was evaluated using WinNonlin software. Human PK profiles were projected based on the PK in monkeys using species-invariant time method. The human efficacious dose projection was based on in vivo nonclinical pharmacological active doses, exposure in mouse infection models and expected human PK. The PK profiles of MHAA4549A and its related antibody showed a linear bi-exponential disposition in mice and cynomolgus monkeys. In mice, clearance and half-life ranged from 5.77 to 9.98 mL/day/kg and 10.2 to 5.76 days, respectively. In cynomolgus monkeys, clearance and half-life ranged from 4.33 to 4.34 mL/day/kg and 11.3 to 11.9 days, respectively. The predicted clearance in humans was ∼2.60 mL/day/kg. A single intravenous dose ranging from 15 to 45 mg/kg was predicted to achieve efficacious exposure in humans. In conclusion, the PK of MHAA4549A was as expected for a human IgG1 monoclonal antibody that lacks known endogenous host targets. The predicted clearance and projected efficacious doses in humans for MHAA4549A have been verified in a Phase 1 study and Phase 2a study, respectively.
authors.affiliation: a Preclinical and Translational Pharmacokinetics Department , Genentech Inc. , South San Francisco , CA , USA.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Gupta
authors.affiliation: a Preclinical and Translational Pharmacokinetics Department , Genentech Inc. , South San Francisco , CA , USA.
authors.forename: Amrita V
authors.initials: AV
authors.lastname: Kamath
authors.affiliation: b Translational Immunology Department , Genentech Inc. , South San Francisco , CA , USA.
authors.forename: Summer
authors.initials: S
authors.lastname: Park
authors.affiliation: c Biochemical and Cellular Pharmacology Department , Genentech Inc. , South San Francisco , CA , USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Chiu
authors.affiliation: a Preclinical and Translational Pharmacokinetics Department , Genentech Inc. , South San Francisco , CA , USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Lutman
authors.affiliation: d Bioanalytical Sciences Department , Genentech Inc. , South San Francisco , CA , USA.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Maia
authors.affiliation: e Infectious Diseases Department , Genentech Inc. , South San Francisco , California , USA.
authors.forename: Man-Wah
authors.initials: MW
authors.lastname: Tan
authors.affiliation: b Translational Immunology Department , Genentech Inc. , South San Francisco , CA , USA.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: f Achaogen , South San Francisco , CA , USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Swem
authors.affiliation: g Clinical Pharmacology Department , Genentech Inc. , South San Francisco , CA , USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Deng
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D000914:Antibodies, Viral / Q000494:pharmacology*; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology; D006801:Humans; D007251:Influenza, Human / Q000188:drug therapy*; D008252:Macaca fascicularis; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008962:Models, Theoretical
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus; C483468:hemagglutinin, human influenza A virus
keywords: Anti-influenza A; antibody; human efficacious dose projection; pharmacokinetics