Preclinical Development – Biomolecular
2019 PharmSci 360
Antibody engineering approaches offer solutions to improve PK properties of protein-based therapeutics. Here, we present a case study where mouse Fc-fusion of a wild type (WT) mouse ligand showed significant PK liability in mice when dosed IV at 1, 3 and 10 mg/kg. The drug concentrations were only detectable within first 6 hours. Therefore, efficacy or PD studies could not be interpreted. Homology modeling enabled us to identify a positive charge cluster on the WT ligand. We engineered the ligand and produced two alternative constructs where the positive charge cluster was removed. The new constructs showed comparable in vitro activity to the WT and exhibited substantial improvement in exposure when dosed IV 5 mg/kg. The dose normalized AUC of the new constructs were 70-100-fold higher compared to the dose normalized AUC of the WT ligand.