Molecular characterization and preclinical efficacy

Abstract

Passive immunotherapy with anti-Abeta antibodies is currently investigated for the treatment of Alzheimer's Disease with several candidates in preclinical or clinical development. BIIB037 was generated using the Reverse Translational Medicine method (RTM). Binding properties of BIIB037 were measured in vitro against soluble and fibrillar Abeta. In vivo studies using Tg2576 mice were conducted to assess brain penetration and binding to amyloid plaques, as well as PK profile of the antibody. Preclinical efficacy was determined after chronic dosing using biochemical and histopathological endpoints. BIIB037 is a fully human IgG1 monoclonal antibody derived from an AD patient with an unusual stable clinical course. The RTM approach was used to isolate, clone and recombinantly express the antibody. In vitro characterization shows a high affinity for insoluble fibrillar human Abeta using an ELISA format assay with fibrillar Abeta1-42 immobilized on the plate, and BIIB037 doesn't bind to soluble Abeta1-40 in an inverted ELISA assay format. Binding was also evaluated using a TAPIR assay and staining of amyloid plaques in both AD brain and transgenic mice brain tissues was observed. BIIB037 enters the brain and binds to amyloid plaques after systemic administration in Tg2576 transgenic mice. The amount of drug detected into the brain is dose-dependent. Chronic dosing for 6 months led to a significant amyloid load reduction as measured by ELISA and histopathology, but didn't lead to increased plasma Abeta1-40, Abeta1-42 levels. Incidence of microhemorrhage and inflammation was not increased compared to vehicle treated group. A novel fully human antibody recognizing fibrillar human Abeta was characterized and its preclinical efficacy was demonstrated in vivo.