Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target

Sci Transl Med. 2011 May 25;3(84):84ra44. doi: 10.1126/scitranslmed.3002230.


Monoclonal antibodies have therapeutic potential for treating diseases of the central nervous system, but their accumulation in the brain is limited by the blood-brain barrier (BBB). Here, we show that reducing the affinity of an antibody for the transferrin receptor (TfR) enhances receptor-mediated transcytosis of the anti-TfR antibody across the BBB into the mouse brain where it reaches therapeutically relevant concentrations. Anti-TfR antibodies that bind with high affinity to TfR remain associated with the BBB, whereas lower-affinity anti-TfR antibody variants are released from the BBB into the brain and show a broad distribution 24 hours after dosing. We designed a bispecific antibody that binds with low affinity to TfR and with high affinity to the enzyme β-secretase (BACE1), which processes amyloid precursor protein into amyloid-β (Aβ) peptides including those associated with Alzheimer's disease. Compared to monospecific anti-BACE1 antibody, the bispecific antibody accumulated in the mouse brain and led to a greater reduction in brain Aβ after a single systemic dose. TfR-facilitated transcytosis of this bispecific antibody across the BBB may enhance its potency as an anti-BACE1 therapy for treating Alzheimer's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / biosynthesis
  • Animals
  • Antibodies / administration & dosage
  • Antibodies / metabolism*
  • Antibodies / therapeutic use*
  • Antibodies, Bispecific / administration & dosage
  • Antibodies, Bispecific / pharmacokinetics
  • Antibodies, Bispecific / therapeutic use
  • Antibody Affinity / immunology*
  • Blood Vessels / metabolism
  • Brain / blood supply
  • Brain / cytology
  • Brain / metabolism*
  • HEK293 Cells
  • Humans
  • Mice
  • Models, Biological
  • Protein Transport
  • Receptors, Transferrin / immunology*
  • Transcytosis / immunology*


  • Amyloid beta-Peptides
  • Antibodies
  • Antibodies, Bispecific
  • Receptors, Transferrin