Abstract
Using therapeutic antibodies that need to cross the blood-brain barrier (BBB) to treat neurological disease is a difficult challenge. We have shown that bispecific antibodies with optimized binding to the transferrin receptor (TfR) that target β-secretase (BACE1) can cross the BBB and reduce brain amyloid-β (Aβ) in mice. Can TfR enhance antibody uptake in the primate brain? We describe two humanized TfR/BACE1 bispecific antibody variants. Using a human TfR knock-in mouse, we observed that anti-TfR/BACE1 antibodies could cross the BBB and reduce brain Aβ in a TfR affinity-dependent fashion. Intravenous dosing of monkeys with anti-TfR/BACE1 antibodies also reduced Aβ both in cerebral spinal fluid and in brain tissue, and the degree of reduction correlated with the brain concentration of anti-TfR/BACE1 antibody. These results demonstrate that the TfR bispecific antibody platform can robustly and safely deliver therapeutic antibody across the BBB in the primate brain.
Copyright © 2014, American Association for the Advancement of Science.
MeSH terms
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Administration, Intravenous
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Amyloid Precursor Protein Secretases / antagonists & inhibitors
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Amyloid Precursor Protein Secretases / immunology*
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Amyloid Precursor Protein Secretases / metabolism
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Amyloid beta-Peptides / cerebrospinal fluid
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Animals
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Antibodies, Bispecific / administration & dosage
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Antibodies, Bispecific / blood
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Antibodies, Bispecific / immunology
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Antibodies, Bispecific / pharmacokinetics*
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Antibody Specificity
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Antigens, CD / genetics
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Antigens, CD / immunology*
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Antigens, CD / metabolism
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Aspartic Acid Endopeptidases / antagonists & inhibitors
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Aspartic Acid Endopeptidases / immunology*
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Aspartic Acid Endopeptidases / metabolism
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Biological Transport
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Blood-Brain Barrier / metabolism*
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CHO Cells
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Capillary Permeability*
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Cricetulus
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Cross Reactions
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Down-Regulation
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HEK293 Cells
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Humans
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Macaca fascicularis
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Transgenic
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Peptide Fragments / cerebrospinal fluid
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Receptors, Transferrin / genetics
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Receptors, Transferrin / immunology*
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Receptors, Transferrin / metabolism
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Transfection
Substances
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Amyloid beta-Peptides
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Antibodies, Bispecific
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Antigens, CD
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CD71 antigen
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Peptide Fragments
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Receptors, Transferrin
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human