A Single Domain Shark Antibody Targeting the Transferrin Receptor 1 Delivers a TrkB Agonist Antibody to the Brain and Provides Full Neuroprotection in a Mouse Model of Parkinson’s Disease
Emily Clarke,
Pawel Stocki,
Elizabeth H. Sinclair,
Aziz Gauhar,
Edward J. R. Fletcher,
Alicja Krawczun-Rygmaczewska,
Susan Duty,
Frank S. Walsh,
Patrick Doherty,
Julia Lynn Rutkowski
Affiliations
Emily Clarke
King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Wolfson Centre for Age-Related Disease, Guy’s Campus, London SE1 1UL, UK
Pawel Stocki
Ossianix, Inc., Gunnels Wood Rd., Stevenage SG1 2FX, UK
Elizabeth H. Sinclair
Ossianix, Inc., Gunnels Wood Rd., Stevenage SG1 2FX, UK
Aziz Gauhar
Ossianix, Inc., Gunnels Wood Rd., Stevenage SG1 2FX, UK
Edward J. R. Fletcher
King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Wolfson Centre for Age-Related Disease, Guy’s Campus, London SE1 1UL, UK
Alicja Krawczun-Rygmaczewska
King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Wolfson Centre for Age-Related Disease, Guy’s Campus, London SE1 1UL, UK
Susan Duty
King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Wolfson Centre for Age-Related Disease, Guy’s Campus, London SE1 1UL, UK
Frank S. Walsh
Ossianix, Inc., Gunnels Wood Rd., Stevenage SG1 2FX, UK
Patrick Doherty
King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Wolfson Centre for Age-Related Disease, Guy’s Campus, London SE1 1UL, UK
Julia Lynn Rutkowski
Ossianix, Inc., Gunnels Wood Rd., Stevenage SG1 2FX, UK
Single domain shark antibodies that bind to the transferrin receptor 1 (TfR1) on brain endothelial cells have been used to shuttle antibodies and other cargos across the blood brain barrier (BBB) to the brain. For these studies the TXB4 brain shuttle was fused to a TrkB neurotrophin receptor agonist antibody. The TXB4-TrkB fusion retained potent agonist activity at its cognate receptor and after systemic administration showed a 12-fold increase in brain levels over the unmodified antibody. Only the TXB4-TrkB antibody fusion was detected within the brain and localized to TrkB positive cells in the cortex and tyrosine hydroxylase (TH) positive dopaminergic neurons in the substantia nigra pars compacta (SNc), where it was associated with activated ERK1/2 signaling. When tested in the 6-hydroxydopamine (6-OHDA) mouse model of Parkinson’s disease (PD), TXB4-TrkB, but not the unmodified antibody, completely prevented the 6-OHDA induced death of TH positive neurons in the SNc. In conclusion, the fusion of the TXB4 brain shuttle allows a TrkB agonist antibody to reach neuroprotective concentrations in the brain parenchyma following systemic administration.
