Therapeutic bispecific antibodies cross the blood-brain barrier in nonhuman primates.
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.
Department of Neuroscience, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Y Joy
YJ
Yu
Department of Neuroscience, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Jasvinder K
JK
Atwal
Antibody Engineering, Genentech Inc., South San Francisco, CA 94080, USA.
Yin
Y
Zhang
Protein Chemistry, Genentech Inc., South San Francisco, CA 94080, USA.
Raymond K
RK
Tong
Development Sciences, Genentech Inc., South San Francisco, CA 94080, USA.
Kristin R
KR
Wildsmith
Antibody Engineering, Genentech Inc., South San Francisco, CA 94080, USA.
Christine
C
Tan
Department of Neuroscience, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Nga
N
Bien-Ly
Department of Neuroscience, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Maria
M
Hersom
Department of Neuroscience, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Janice A
JA
Maloney
Department of Neuroscience, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
William J
WJ
Meilandt
Development Sciences, Genentech Inc., South San Francisco, CA 94080, USA.
Daniela
D
Bumbaca
Development Sciences, Genentech Inc., South San Francisco, CA 94080, USA.
Kapil
K
Gadkar
Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA 94080, USA.
Kwame
K
Hoyte
Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA 94080, USA.
Wilman
W
Luk
Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA 94080, USA.
Yanmei
Y
Lu
Protein Chemistry, Genentech Inc., South San Francisco, CA 94080, USA.
James A
JA
Ernst
Department of Neuroscience, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Kimberly
K
Scearce-Levie
Development Sciences, Genentech Inc., South San Francisco, CA 94080, USA.
Jessica A
JA
Couch
Antibody Engineering, Genentech Inc., South San Francisco, CA 94080, USA.
Mark S
MS
Dennis
Department of Neuroscience, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. rwatts@gene.com.
Ryan J
RJ
Watts
D061605:Administration, Intravenous; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D000818:Animals; D018033:Antibodies, Bispecific / Q000008:administration & dosage / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics*; D000918:Antibody Specificity; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D016466:CHO Cells; D002199:Capillary Permeability; D003412:Cricetulus; D003429:Cross Reactions; D015536:Down-Regulation; D057809:HEK293 Cells; D006801:Humans; D008252:Macaca fascicularis; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D011990:Receptors, Transferrin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014162:Transfection
D016229:Amyloid beta-Peptides; D018033:Antibodies, Bispecific; D015703:Antigens, CD; C068126:CD71 antigen; D010446:Peptide Fragments; D011990:Receptors, Transferrin; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human