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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...

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Autores principales: Lessard, Etienne, Rennie, Kerry, Haqqani, Arsalan, Ling, Binbing, Whitfield, James, Paradis, Andrea, Araujo, Joseph, Yoganathan, Nathan, Gillard, John, Stanimirovic, Danica, Chakravarthy, Balu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9246806/
https://www.ncbi.nlm.nih.gov/pubmed/35704250
http://dx.doi.org/10.1007/s11095-022-03285-z
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author Lessard, Etienne
Rennie, Kerry
Haqqani, Arsalan
Ling, Binbing
Whitfield, James
Paradis, Andrea
Araujo, Joseph
Yoganathan, Nathan
Gillard, John
Stanimirovic, Danica
Chakravarthy, Balu
author_facet Lessard, Etienne
Rennie, Kerry
Haqqani, Arsalan
Ling, Binbing
Whitfield, James
Paradis, Andrea
Araujo, Joseph
Yoganathan, Nathan
Gillard, John
Stanimirovic, Danica
Chakravarthy, Balu
author_sort Lessard, Etienne
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11095-022-03285-z.
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spelling pubmed-92468062022-07-02 Pharmacokinetics and Pharmacodynamic Effect of a Blood-Brain Barrier-Crossing Fusion Protein Therapeutic for Alzheimer’s Disease in Rat and Dog Lessard, Etienne Rennie, Kerry Haqqani, Arsalan Ling, Binbing Whitfield, James Paradis, Andrea Araujo, Joseph Yoganathan, Nathan Gillard, John Stanimirovic, Danica Chakravarthy, Balu Pharm Res Research Paper 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11095-022-03285-z. Springer US 2022-06-15 2022 /pmc/articles/PMC9246806/ /pubmed/35704250 http://dx.doi.org/10.1007/s11095-022-03285-z Text en © Crown 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Paper
Lessard, Etienne
Rennie, Kerry
Haqqani, Arsalan
Ling, Binbing
Whitfield, James
Paradis, Andrea
Araujo, Joseph
Yoganathan, Nathan
Gillard, John
Stanimirovic, Danica
Chakravarthy, Balu
Pharmacokinetics and Pharmacodynamic Effect of a Blood-Brain Barrier-Crossing Fusion Protein Therapeutic for Alzheimer’s Disease in Rat and Dog
title Pharmacokinetics and Pharmacodynamic Effect of a Blood-Brain Barrier-Crossing Fusion Protein Therapeutic for Alzheimer’s Disease in Rat and Dog
title_full Pharmacokinetics and Pharmacodynamic Effect of a Blood-Brain Barrier-Crossing Fusion Protein Therapeutic for Alzheimer’s Disease in Rat and Dog
title_fullStr Pharmacokinetics and Pharmacodynamic Effect of a Blood-Brain Barrier-Crossing Fusion Protein Therapeutic for Alzheimer’s Disease in Rat and Dog
title_full_unstemmed Pharmacokinetics and Pharmacodynamic Effect of a Blood-Brain Barrier-Crossing Fusion Protein Therapeutic for Alzheimer’s Disease in Rat and Dog
title_short Pharmacokinetics and Pharmacodynamic Effect of a Blood-Brain Barrier-Crossing Fusion Protein Therapeutic for Alzheimer’s Disease in Rat and Dog
title_sort pharmacokinetics and pharmacodynamic effect of a blood-brain barrier-crossing fusion protein therapeutic for alzheimer’s disease in rat and dog
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9246806/
https://www.ncbi.nlm.nih.gov/pubmed/35704250
http://dx.doi.org/10.1007/s11095-022-03285-z
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