Efficacy of A/H1N1/2009 split inactivated influenza A vaccine (GC1115) in mice and ferrets.

To evaluate the efficacy of a non-adjuvant A/H1N1/2009 influenza A vaccine (GC1115), we demonstrated the immunogenicity and protective efficacy of GC1115 in mouse and ferret models. The immunogenicity of GC1115 was confirmed after intramuscular administration of 1.875, 3.75, 7.5, and 15 µg hemagglutinin antigen (HA) in mice and 7.5, 15, and 30 µg HA in ferrets at 3-week intervals. A single immunization with GC1115 at HA doses > 7.5 µg induced detectable seroconversion in most mice, and all mice given a second dose exhibited high antibody responses in a dose-dependent manner. The mice in the mock (PBS) and 1.875 µg HA immunized groups succumbed by 13 days following A/California/ 04/09 infection, while all mice in groups given more than 3.75 µg HA were protected from lethal challenge with the A/California/04/09 virus. In ferrets, although immunization with even a single dose of 15 or 30 µg of HA induced detectable HI antibodies, all ferrets given two doses of vaccine seroconverted and exhibited HI titers greater than 80 units. Following challenge with A/California/04/09, the mock (PBS) immunized ferrets showed influenza-like clinical symptoms, such as increased numbers of coughs, elevated body temperature, and body weight loss, for 7 days, while GC1115- immunized ferrets showed attenuated clinical symptoms only for short time period (3-4 days). Further, GC1115-immunized ferrets displayed significantly lower viral titers in the upper respiratory tract (nasal cavity) than the mock vaccinated group in a dose-dependent manner. Taken together, this study demonstrates the immunogenicity and protective efficacy of GC1115 as a non-adjuvanted vaccine.

Use of a Target-Mediated Drug Disposition Model to Predict the Human Pharmacokinetics and Target Occupancy of GC1118, an Anti-epidermal Growth Factor Receptor Antibody.

GC1118 is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody that is currently under clinical development. In this study, the pharmacokinetics (PK) of GC1118 were modelled in monkeys to predict human PK and receptor occupancy (RO) profiles. The serum concentrations of GC1118 and its comparator (cetuximab) were assessed in monkeys with a non-compartmental analysis and a target-mediated drug disposition (TMDD) model after intravenous infusion (3-25 mg/kg) of these drugs. The scaling exponent of the EGFR synthesis rate was determined using a sensitivity analysis. The human cetuximab exposures were simulated by applying different exponents (0.7-1.0) for the EGFR synthesis rate in the allometric monkey PK model. Simulated Cmax and area under the curve values therein were compared with those previously reported in the literature to find the best exponent for the EGFR synthesis rate in human beings. The TMDD model appropriately described the monkey PK profile, which showed a decrease in clearance (CL; 1.2-0.4 ml/hr/kg) as the dose increased. The exponents for CL (0.75) and volume of distribution (Vd; 1.0) were used for the allometric scaling to predict human PK. The allometric coefficient for the EGFR synthesis rate chosen by the sensitivity analysis was 0.85, and the RO profiles that could not be measured experimentally were estimated based on the predicted concentrations of the total target and the drug-target complex. Our monkey TMDD model successfully predicts human PK and RO profiles of GC1118 and can be used to determine the appropriate dose for a first-in-human study investigating this drug.