Bispecific antibodies (bAbs) that engage cerebrovascular targets, induce transport across the blood-brain barrier (BBB), and redistribute to secondary targets within the brain parenchyma have the potential to transform the diagnosis and treatment of a wide range of central nervous system disorders. Full understanding of the pharmacokinetics (PK) of these agents, including their potential for delivering cargo into brain parenchymal cells, is a key priority for the development of numerous potential therapeutic applications. To date, the brain PK of bAbs that target transferrin receptor (TfR-1) and CD98 heavy chain (CD98hc) has been characterized using techniques incapable of distinguishing between CNS clearance of intact protein from uptake and catabolism by brain parenchymal cells. Herein, we address this knowledge gap via a comparative radiotracing strategy using two radioisotopes with distinct residualizing properties, iodine-125 (I-125) and zirconium-89 (Zr-89). We first identify reaction conditions for tetravalent chelator modification and Zr-89 radiolabeling that do not adversely affect in vitro or in vivo function. We then use comparative radiotracing to define the PK of TfR-1 and CD98hc targeted bAbs without a parenchymal target, generating quantitative evidence of TfR-1-mediated cellular uptake and catabolism that implicates these processes in previously reported differences in the brain retention of IgGs shuttled across the BBB via these two pathways. Finally, we perform comparative radiotracing on a TfR-1 bAb with an internalizing neuronal target (TrkB), demonstrating rapid divergence of Zr-89 and I-125 PK curves, with a > 30-fold difference in brain content of the two radioisotopes. Together, these results establish comparative radiotracing as a valuable technique for identifying internalizing cellular targets within the brain parenchyma and quantifying the extent and timing of bAb uptake and catabolism following target engagement.

Pharmaceutics

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

Article

Author: Rutkowski, Julia Lynn ; Gauhar, Aziz ; Duty, Susan ; Fletcher, Edward J. R. ; Stocki, Pawel ; Krawczun-Rygmaczewska, Alicja ; Clarke, Emily ; Doherty, Patrick ; Walsh, Frank S. ; Sinclair, Elizabeth H.

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.

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