O1‐06‐02: Enhancing antibody uptake in brain to target BACE1

Abstract

Boosting antibody uptake in brain would substantially improve our ability to modulate various CNS drug targets. To better understand antibody properties relative to the blood-brain barrier (BBB) and as a potential Alzheimer's therapeutic intervention, we developed an antibody that targets BACE1. By utilizing a receptor-mediated transcytosis approach targeting the transferrin receptor (TfR), we explored how we could enhance uptake of our therapeutic antibody across the BBB. A function-blocking antibody targeting BACE1 (anti-BACE1) was developed and characterized in vitro. A bispecific antibody with low affinity to TfR and with high affinity to BACE1 (anti-TfR/BACE1) was generated to enhance brain uptake. Brain antibody levels and Abeta reduction were evaluated following systemic delivery of anti-BACE1 or anti-TfR/BACE1 in mice. Anti-BACE1 is a highly selective, potent antagonist of BACE1 that inhibits BACE1 activity by binding to an exosite. Anti-BACE1 reduces Abeta production in cultured human cell lines expressing APP and in primary mouse neurons. Systemic dosing of mice with anti-BACE1 resulted in sustained reductions in peripheral Abeta concentrations. High doses of anti-BACE1 also transiently reduced CNS Abeta concentrations. Enhancing brain uptake of anti-BACE1 by utilizing a bispecific anti-TfR/BACE1 resulted in substantially improved brain exposure leading to a greater and more sustained reduction in brain Abeta with lower dose levels than anti-BACE1 alone. BACE1 can be targeted in a highly selective manner through passive immunization with BBB penetrating anti-TfR/BACE1 antibodies. These data also provide proof-of-concept for brain penetrating antibodies, expanding our ability to develop CNS antibody therapies.