OO019 - FACTORS GOVERNING RECEPTOR-MEDIATED BRAIN DELIVERY OF BISPECIFIC ANTIBODIES (ID 996)
Abstract
Aims
Objectives: Bispecific antibodies targeting amyloid-beta (Aβ) and the transferrin receptor (TfR) could be used for immunotherapy, or when radiolabelled, as positron emission tomography (PET) tracers in in Alzheimer’s Disease (AD). The aim of this study was to investigate in mice how TfR mediated brain delivery of such bispecific antibodies is affected by factors like antibody format, dose, blood cell binding and age of the mice.
Methods
Methods: Biodistribution of two formats of iodinated bispecific antibody ligands mAb3D6-scFv8D3 (210 kDA) and di-scFv3D6-8D3 (58 kDa) were investigated ex vivo, in wild type mice. Brain concentration and plasma/blood cell distribution of [125I]mAb3D6-scFv8D3 was compared between young and old, wild type (WT) and AD transgenic (tg-ArcSwe) mice, at two different doses. Capillary depletion and nuclear track emulsion was used to study brain parenchymal-vascular distribution of the antibodies.
Results
Results: The smaller format antibody displayed lower total brain concentration, but had a faster parenchymal delivery, and higher parenchymal-to-vascular concentration ratio. Young WT mice showed a significantly higher total brain concentration 2 h after administration of [125I]mAb3D6-scFv8D3, compared to old mice. At low dosing, [125I]mAb3D6-scFv8D3 was associated with higher distribution to blood cells, and thereby lower plasma concentration, compared to high dosing. At low dosing, plasma concentration was a better predictor of [125I]mAb3D6-scFv8D3 brain delivery, compared to whole blood concentration.
Conclusions
Conclusions: Small format antibodies, with monovalent binding towards TfR have faster parenchymal delivery. At low doses, TfR-antibodies display higher blood cell binding, which could affect brain uptake at early time points in aged mice.
