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The TransMission: SNiP

Crossing the BBB with Nanobodies

Last Updated: August 24, 2023

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The blood brain barrier protects our brains from circulating pathogens and inflammatory cells. However, it also prevents the delivery of therapeutics into the brain. One effective strategy for crossing into this privileged space is through interaction with receptors at its interface, such as the transferrin receptor (TfR).

In this study, the authors engineered a bispecific antibody that binds both TfR and the drug target BACE1, an enzyme whose activity has been linked to Alzheimer's disease.1 (See [2] for a Perspective article on the promises and challenges associated with targeting BACE1 in recent clinical trials.)

Nanobody TfR BBB Diagram
Figure 1. Diagram of bispecific anti-BACE1 and transferrin receptor (TfR) nanobody construct

The construction of bispecific antibodies was enabled by nanobody technology paired with a 'knobs-into-holes' design of the antibody's heavy chain (Figure 1). One "half" of the antibody binds BACE1 to inhibit its activity. The other "half," which binds TfR, was identified by immunizing alpacas with a chimeric macaque-alpaca TfR construct to produce a nanobody library. The library was then screened with phage display panned against TfR-overexpressing CHO cells to find nanobodies that bind human and macaque TfR with high affinity.

The authors show that their anti-BACE1 and TfR nanobody construct was able to bind BACE1 with sub-nanomolar affinity in vitro. A reduction of the Alzheimer’s disease marker Aβ in the blood as well as the brain was also observed when the antibody was injected intravenously in a humanized TfR mouse model. Notably, the ability to function in multiple model species is significant for preclinical drug development and testing.


Title: Novel Human/Non-Human Primate Cross-Reactive Anti-Transferrin Receptor Nanobodies for Brain Delivery of Biologics
Authors: Laura Rué, Tom Jaspers et al.
Journal: Pharmaceutics, Volume 15, June 2023.
DOI: 10.3390/pharmaceutics15061748

Product Usage: Stable cell lines that overexpressed macaque or human TfR for phage display were generated using TransIT-PRO® Transfection Reagent in adherent CHO cells. Expression of the bispecific anti-BACE1 and TfR nanobody constructs for characterization and in vivo studies was performed in suspension ExpiCHO-S cells using the CHOgro® High Yield Expression System.

Visit the Mirus Bio Citations Database to see more ways CHOgro® has been used for protein production experiments!



  1. S. Sinha, et al., Nature (1999).
    DOI: 10.1038/990114
  2. E. McDade, et al., Nature Reviews Neurology (2021).
    DOI: 10.1038/s41582-021-00545-1


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