Engineered Bispecific Antibody Shuttles Unlock Dual-Receptor Pathway Across the Blood–Brain Barrier
核心洞察
Researchers engineered Brainshuttle™ antibody variants targeting TfR1 (搜索) and CD98hc (搜索) to enhance delivery of antisense oligonucleotides across the blood–brain barrier.
A bispecific dual-targeting approach combined TfR1 (搜索)'s efficient uptake with CD98hc (搜索)'s prolonged cellular residence, strengthening BBB transport in cellular models.
ASO cargo attachment altered receptor binding behavior, improving uptake for lower-affinity shuttles while reducing engagement for higher-affinity variants.
A significant advance in overcoming one of neurology's most persistent drug delivery challenges has been reported, with researchers demonstrating that engineered bispecific antibody shuttles can ferry antisense oligonucleotides (ASOs) across the blood–brain barrier (BBB) through a novel dual-receptor mechanism. The findings, published in mAbs, provide critical design principles for developing central nervous system (CNS) delivery platforms that could expand the therapeutic reach of RNA-based medicines.
ASOs can precisely regulate disease-related genes, but their clinical utility has been severely constrained by an inability to cross the BBB in meaningful quantities. While transferrin receptor (TfR1 (搜索))-mediated shuttling has previously shown encouraging results, the underlying molecular mechanisms have remained largely unknown.
ASO Cargo Modulates Receptor Engagement
In the study, researchers optimized TfR1 (搜索) binding by attaching ASOs to engineered antibody shuttles and systematically investigated their interaction with endothelial cells. The results revealed a nuanced relationship between cargo and receptor: ASO attachment improved binding and uptake for some lower-affinity TfR1-targeting shuttles, but reduced receptor engagement for higher-affinity shuttles. "This highlights that ASO structure and payload can alter how the antibody binds, enters, and moves through BBB cells," the authors noted.
CD98hc (搜索) Emerges as an Alternative BBB Receptor
The team also investigated CD98hc (搜索), an alternative BBB receptor, as a potential delivery target. CD98hc followed a different cellular transport pathway and showed a more favorable response to ASO conjugation compared to TfR1 (搜索). Critically, this target helped avoid degradation pathways and peripheral clearance, positioning CD98hc as a promising alternative for future CNS therapies.
Bispecific Design Amplifies Transport Efficiency
Building on these insights, researchers created a bispecific antibody designed to target both TfR1 (搜索) and CD98hc (搜索) simultaneously. The dual-targeting system combined the efficient uptake properties of TfR1 with the prolonged cellular residence associated with CD98hc, supporting stronger transport across BBB models than either receptor target alone.
Functional Activity Confirmed in Neuronal Models
The delivered ASOs successfully reduced target RNA levels in neuron models, confirming functional activity after transport across the barrier. This demonstration of post-transport gene silencing underscores the therapeutic potential of the approach for neurological disorders, including neurodegenerative diseases (搜索).
The study, conducted by Sela T et al. and published in mAbs (DOI:10.1080/19420862.2026.2691351), employed Brainshuttle™ technology to generate the mono- and bispecific TfR- and CD98-targeting variants. Further studies are needed to confirm whether the approach translates into improved delivery and efficacy in animal models and clinical settings.