A peptide derived from melanotransferrin delivers a protein-based interleukin 1 receptor antagonist across the BBB and ameliorates neuropathic pain in a preclinical model

Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism
George ThomReinhard Gabathuler

Abstract

Delivery of biologic drugs across the blood-brain barrier is becoming a reality. However, the solutions often involve the assembly of complex multi-specific antibody molecules. Here we utilize a simple 12 amino-acid peptide originating from the melanotransferrin (MTf) protein that has shown improved brain delivery properties. 3D confocal fluorescence microscopic analysis demonstrated brain parenchymal localisation of a fluorescently labelled antibody (NIP228) when chemically conjugated to either the MTf peptide or full-length MTf protein. Measurement of plasma kinetics demonstrated the MTf peptide fusions had very similar kinetics to an unmodified NIP228 control antibody, whereas the fusion to MTf protein had significantly reduced plasma exposure most likely due to a higher tissue distribution in the periphery. Brain exposure for the MTf peptide fusions was significantly increased for the duration of the study, exceeding that of the fusions to full length MTf protein. Using a neuropathic pain model, we have demonstrated that fusions to interleukin-1 receptor antagonist (IL-1RA) are able to induce significant and durable analgesia following peripheral administration. These data demonstrate that recombinant and chemically conjuga...Continue Reading

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Citations

Jul 3, 2020·Chemical & Pharmaceutical Bulletin·Koki OgawaShigeru Kawakami
Mar 7, 2020·Fluids and Barriers of the CNS·Richard F KeepLester R Drewes
Jan 29, 2019·Frontiers in Neuroscience·Victor M Pulgar
Jul 13, 2020·Biochemical Pharmacology·Gabor TajtiRaymond S Norton
Feb 6, 2021·International Journal of Pharmaceutics·Manisha ChoudhariSunil Kumar Dubey
Apr 20, 2021·Frontiers in Molecular Biosciences·Brett A EyfordWilfred A Jefferies

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Methods Mentioned

BETA
size exclusion chromatography
PCR
fluorescence
confocal microscopy
sandwich immunoassay
dissection
fluorescence microscopy

Software Mentioned

ARRIVE
WinNonlin Phoenix
Phoenix WinNonlin Professional
Agilent Quantitation
Imaris
MassHunter Worstation

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