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

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

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.

MeSH terms

  • Animals
  • Antibodies, Bispecific / administration & dosage*
  • Antibodies, Bispecific / chemistry
  • Antibodies, Bispecific / metabolism
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism
  • Brain / drug effects*
  • Brain / metabolism
  • Drug Delivery Systems / methods*
  • Drug Design*
  • Humans
  • Macaca fascicularis
  • Prospective Studies
  • Receptors, Transferrin / antagonists & inhibitors*
  • Receptors, Transferrin / metabolism

Substances

  • Antibodies, Bispecific
  • Receptors, Transferrin