Pharmacokinetics and Pharmacodynamic Effect of a Blood-Brain Barrier-Crossing Fusion Protein Therapeutic for Alzheimer's Disease in Rat and Dog

Purpose We have recently demonstrated the brain-delivery of an Amyloid-ss oligomer (Asso)-binding peptide-therapeutic fused to the BBB-crossing single domain antibody FC5. The bi-functional fusion protein, FC5-mFc-ABP (KG207-M) lowered both CSF and brain Ass levels after systemic dosing in transgenic mouse and rat models of Alzheimer's disease (AD). For development as a human therapeutic, we have humanized and further engineered the fusion protein named KG207-H. The purpose of the present study was to carry out comparative PK/PD studies of KG207-H in wild type rat and beagle dogs (middle-aged and older) to determine comparability of systemic PK and CSF exposure between rodent species and larger animals with more complex brain structure such as dogs. Method Beagle dogs were used in this study as they accumulate cerebral Ass with age, as seen in human AD patients, and can serve as a model of sporadic AD. KG207-H (5 to 50 mg/kg) was administered intravenously and serum and CSF samples were serially collected for PK studies and to assess target engagement. KG207-H and A beta levels were quantified using multiplexed selected reaction monitoring mass spectrometry. Results After systemic dosing, KG207-H demonstrated similar serum pharmacokinetics in rats and dogs. KG207-H appeared in the CSF in a time- and dose-dependent manner with similar kinetics, indicating CNS exposure. Further analyses revealed a dose-dependent inverse relationship between CSF KG207-H and Ass levels in both species indicating target engagement. Conclusion This study demonstrates translational attributes of BBB-crossing A beta-targeting biotherapeutic KG207-H in eliciting a pharmacodynamic response, from rodents to larger animal species.

Automated summary

This study demonstrates the translational attributes of the BBB-crossing A beta-targeting biotherapeutic KG207-H in eliciting a pharmacodynamic response, from rodents to larger animal species. The study compares the PK/PD of KG207-H in wild type rat and beagle dogs and shows similar serum pharmacokinetics and CNS exposure in both species.