Lack of Widespread BBB Disruption in Alzheimer's Disease Models: Focus on Therapeutic Antibodies.
The blood-brain barrier (BBB) limits brain uptake of therapeutic antibodies. It is believed that the BBB is disrupted in Alzheimer's disease (AD), potentially increasing drug permeability de facto. Here we compared active versus passive brain uptake of systemically dosed antibodies (anti-transferrin receptor [TfR] bispecific versus control antibody) in mouse models of AD. We first confirmed BBB disruption in a mouse model of multiple sclerosis as a positive control. Importantly, we found that BBB permeability was vastly spared in mouse models of AD, including PS2-APP, Tau transgenics, and APOE4 knockin mice. Brain levels of TfR in mouse models or in human cases of AD resembled controls, suggesting target engagement of TfR bispecific is not limited. Furthermore, infarcts from human AD brain showed similar occurrences compared to age-matched controls. These results question the widely held view that the BBB is largely disrupted in AD, raising concern about assumptions of drug permeability in disease.
Department of Neuroscience, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: bienly.nga@gene.com.
Nga
N
Bien-Ly
Department of Development Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
C Andrew
CA
Boswell
Department of Translational Immunology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Surinder
S
Jeet
Banner Sun Health Research Institutes, 10515 West Santa Fe Drive, Sun City, AZ 85372, USA.
Thomas G
TG
Beach
Department of Biochemical and Cellular Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Kwame
K
Hoyte
Department of Biochemical and Cellular Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Wilman
W
Luk
Department of Biochemical and Cellular Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Vera
V
Shihadeh
Department of Development Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Sheila
S
Ulufatu
Department of Pathology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Oded
O
Foreman
Department of Biochemical and Cellular Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Yanmei
Y
Lu
Department of Translational Immunology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Jason
J
DeVoss
Department of Diagnostic Discovery, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: vanderbrug.marcel@gene.com.
Marcel
M
van der Brug
Department of Neuroscience, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Ryan J
RJ
Watts
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000906:Antibodies / Q000378:metabolism* / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D057127:Single-Chain Antibodies / Q000378:metabolism
D000906:Antibodies; C090089:EDNsFv anti-transferrin receptor; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies