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

George Thom, Mei Mei Tian, Jon P. Hatcher, Natalia Rodrigo, Matthew Burrell, Ian Gurrell, Timothy Z. Vitalis, Thomas Abraham, Wilfred A. Jefferies, Carl I. Webster, Reinhard Gabathuler

Research output: Contribution to journalArticle

2 Scopus citations

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 conjugated MTf-based brain delivery vectors can deliver therapeutic levels of drug to the central nervous system.

Original languageEnglish (US)
Pages (from-to)2074-2088
Number of pages15
JournalJournal of Cerebral Blood Flow and Metabolism
Volume39
Issue number10
DOIs
StatePublished - Oct 1 2019

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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