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

Autor: Kanodia, JS, Gadkar, K, Bumbaca, D, Zhang, Y, Tong, RK, Luk, W, Hoyte, K, Lu, Y, Wildsmith, KR, Couch, JA, Watts, RJ, Dennis, MS, Ernst, JA, Scearce‐Levie, K, Atwal, JK, Ramanujan, S, Joseph, S
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Zdroj: CPT: Pharmacometrics & Systems Pharmacology; May2016, Vol. 5 Issue 5, p283-291, 9p
Abstrakt: 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. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index