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

Abstract

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 Aβ 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 Aβ-targeting biotherapeutic KG207-H in eliciting a pharmacodynamic response, from rodents to larger animal species.

Recent Advances in Modified Brain‐Targeting Drug Delivery Systems for Erythropoietin

“…It can specifically bind and enter human brain endothelial cells. [55,56] FC5 can deliver the neuropeptide dalargin and IgG fusion proteins across the BBB. [57] A bifunctional fusion protein in which FC5 was fused to an amyloid-𝛽-binding peptide via a mouse IgG2a Fc fragment was successfully transported into the brain of rats and dogs with AD and was associated with significantly improved pathology.…”

“…Specific BBB receptor ligand-modified nanomaterials help to increase targeting effects and reduce therapeutic doses and side effects. [56] Fifth, the three kinds of modified EPO maintain hematopoietic activity and have an erythropoietic effect. However, the intensity of the effect is lesser than that of native EPO.…”

“…[ 57 ] A bifunctional fusion protein in which FC5 was fused to an amyloid‐β‐binding peptide via a mouse IgG2a Fc fragment was successfully transported into the brain of rats and dogs with AD and was associated with significantly improved pathology. [ 56 ] The construction of a novel EPO fusion protein combined with antibodies against these more specific BBB targets might be an alternative strategy to enhance the efficiency of the brain delivery system.…”

“…Specific BBB receptor ligand‐modified nanomaterials help to increase targeting effects and reduce therapeutic doses and side effects. [ 56 ]…”

Multiphysics Simulation in Drug Development and Delivery

“…The combination with pharmacodynamics (PD) models further enable describing the response of the studied system to drugs. Given these advantages, PK/PD models have been seen significant adoption to optimise dose and regimen [13], develop effective drugs [14], scale laboratory experiments to clinical trials [15], and explore and examine the physiological barriers in drug delivery [16], particularly the delivery to the central nervous system [17,18]. Unlike PK/PD models, transport-based models are able to accommodate the realistic geometry of the entire tissue or tissue microstructure for outputting both the temporal drug concentration and spatial distribution.…”