Prospective Design of Anti-Transferrin Receptor Bispecific Antibodies for Optimal Delivery into the Human Brain.
Anti-transferrin receptor (TfR)-based bispecific antibodies have shown promise for boosting antibody uptake in the brain. Nevertheless, there are limited data on the molecular properties, including affinity required for successful development of TfR-based therapeutics. A complex nonmonotonic relationship exists between affinity of the anti-TfR arm and brain uptake at therapeutically relevant doses. However, the quantitative nature of this relationship and its translatability to humans is heretofore unexplored. Therefore, we developed a mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model for bispecific anti-TfR/BACE1 antibodies that accounts for antibody-TfR interactions at the blood-brain barrier (BBB) as well as the pharmacodynamic (PD) effect of anti-BACE1 arm. The calibrated model correctly predicted the optimal anti-TfR affinity required to maximize brain exposure of therapeutic antibodies in the cynomolgus monkey and was scaled to predict the optimal affinity of anti-TfR bispecifics in humans. Thus, this model provides a framework for testing critical translational predictions for anti-TfR bispecific antibodies, including choice of candidate molecule for clinical development.
Preclinical and Translational Pharmacokinetics Department, Genentech, South San Francisco, California, USA.
J S
JS
Kanodia
Preclinical and Translational Pharmacokinetics Department, Genentech, South San Francisco, California, USA.
K
K
Gadkar
Preclinical and Translational Pharmacokinetics Department, Genentech, South San Francisco, California, USA.
D
D
Bumbaca
Antibody Engineering Department, Genentech, South San Francisco, California, USA.
Y
Y
Zhang
Protein Sciences, Genentech, South San Francisco, California, USA.
R K
RK
Tong
Biochemical and Cellular Pharmacology, Genentech, South San Francisco, California, USA.
W
W
Luk
Biochemical and Cellular Pharmacology, Genentech, South San Francisco, California, USA.
K
K
Hoyte
Biochemical and Cellular Pharmacology, Genentech, South San Francisco, California, USA.
Y
Y
Lu
Biomarker Development, Genentech, South San Francisco, California, USA.
K R
KR
Wildsmith
Safety Assessment, Genentech, South San Francisco, California, USA.
J A
JA
Couch
Department of Neuroscience, Genentech, South San Francisco, California, USA.
R J
RJ
Watts
Antibody Engineering Department, Genentech, South San Francisco, California, USA.
M S
MS
Dennis
Protein Sciences, Genentech, South San Francisco, California, USA.
J A
JA
Ernst
Department of Neuroscience, Genentech, South San Francisco, California, USA.
K
K
Scearce-Levie
Department of Neuroscience, Genentech, South San Francisco, California, USA.
J K
JK
Atwal
Preclinical and Translational Pharmacokinetics Department, Genentech, South San Francisco, California, USA.
S
S
Ramanujan
Preclinical and Translational Pharmacokinetics Department, Genentech, South San Francisco, California, USA.
S
S
Joseph
D000818:Animals; D018033:Antibodies, Bispecific / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D015195:Drug Design; D006801:Humans; D008252:Macaca fascicularis; D011446:Prospective Studies; D011990:Receptors, Transferrin / Q000037:antagonists & inhibitors* / Q000378:metabolism
D018033:Antibodies, Bispecific; D011990:Receptors, Transferrin