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.

Tutorial on Monoclonal Antibody Pharmacokinetics and Its Considerations in Early Development

“…Projecting human efficacious dose is based on two key assumptions: exposure–response relationships translate across species and mAb PK is predictable in humans at a relevant dose range. It includes the following steps: 1) define the efficacy end points and establish an exposure–response relationships in the efficacy model; 2) project human PK profiles from cynomolgus monkey using a simplified allometric scaling or time‐invariant time method (TMDD modeling if expecting nonlinear PK); and 3) integrate efficacy PK/PD models with human PK projections and estimate human efficacious dose …”

Passive immunization for influenza through antibody therapies, a review of the pipeline, challenges and potential applications

“…The mAb has been show to neutralize all seasonal influenza A viruses [20]. It has also been evaluated and shown to be effective in mice and ferret challenge studies against H5N1 virus [21].…”

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Study To Investigate the Safety, Tolerability, and Pharmacokinetics of an Anti-Influenza B Virus Monoclonal Antibody, MHAB5553A, in Healthy Volunteers

“…The human efficacious dose of MHAB5553A is expected to be the same as that for MHAA4549A, a broadly neutralizing monoclonal IgG1 antibody that targets influenza A virus HA (25,26), based upon their similar mechanisms of action, comparable in vitro binding properties, comparable PK in mice and monkeys, and the same efficacious dose range in mouse influenza infection models (23,25,27,28). MHAA4549A also demonstrated strong antiviral activity at 3,600 mg in healthy volunteers challenged with influenza A virus (29).…”