Very intriguing paper on antibodies equipped with binding domains for both the TfR1 and CD98hc receptors (found abundantly on the blood-brain-barrier). Brain uptake was enhanced by using binding domains for both receptors. Wells et al. also varied the TfR1/CD98hc affinities of the binding domains and explored how different combinations of affinities influenced brain uptake and localization within the brain. Interestingly, higher CD98hc affinity made the antibody brain concentration peak at 7 days post-injection whereas higher TfR1 affinity made the antibody brain concentration peak at 1 day post-injection. Additionally, stronger CD98hc binding led to more astrocyte localization while stronger TfR1 binding led to more neuronal localization.

Wells et al. developed a dual-targeting transport vehicle binding both transferrin receptor and CD98hc, two proteins highly expressed at the blood-brain barrier. Through affinity tuning, the authors demonstrated that brain concentration, kinetics, and cellular distribution can be modulated, offering a versatile platform for CNS delivery of biotherapeutics.