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CPT Pharmacometrics Syst Pharmacol. 2016 May;5(5):283-91. doi: 10.1002/psp4.12081. Epub 2016 May 17.

Prospective Design of Anti-Transferrin Receptor Bispecific Antibodies for Optimal Delivery into the Human Brain.

Author information

1
Preclinical and Translational Pharmacokinetics Department, Genentech, South San Francisco, California, USA.
2
Antibody Engineering Department, Genentech, South San Francisco, California, USA.
3
Protein Sciences, Genentech, South San Francisco, California, USA.
4
Biochemical and Cellular Pharmacology, Genentech, South San Francisco, California, USA.
5
Biomarker Development, Genentech, South San Francisco, California, USA.
6
Safety Assessment, Genentech, South San Francisco, California, USA.
7
Department of Neuroscience, Genentech, South San Francisco, California, USA.

Abstract

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.

PMID:
27299941
PMCID:
PMC4879477
DOI:
10.1002/psp4.12081
[Indexed for MEDLINE]
Free PMC Article

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