A novel recombinant human amyloid plaque-specific antibody for the treatment of Alzheimer's disease: Molecular properties and preclinical efficacy

Preclinical profile of Aβ binding properties and efficacy of a fully human monoclonal anti-Aβ antibody. Binding properties were assessed by Biacore and X-ray crystallography. In life efficacy for plaque binding and Aβ clearance was characterized by immunoassays and quantitative image analysis. Anti Aβ antibodies are currently explored as promising therapeutics to treat Alzheimer's disease (AD). We have generated a new type of a human recombinant antibody with amyloid plaque specificity by phage display and in vitro maturation technologies. Antibody binding properties were optimized to achieve subnanomolar affinity and strong reactivity with human amyloid plaques and maximal target occupancy in vivo. A conformation specific binding mode was indicated by higher binding affinity to fibrillar versus monomeric Aβ40/42. Epitope mapping with linear Aβ decapeptides showed reactivity against N-terminal (EFRHDSGYE) and central (FFAEDVGS) amino acids, suggesting recognition of a unique structure present on Aβ fibrils. X-ray crystallography revealed an interesting binding mode involving multiple amino acids of heavy and light chain CDRs and all residues of Aβ 3-11. In vivo, the human antibody entered the brain and efficiently co-localized to all types of plaques in APPswe x PS2N141I (PS2APP) mice. Plaque binding was dose-dependent with a minimal effective dose of 0.1 mg/kg and detectable over 2 months after single administration. Chronic treatment of PS2APP mice revealed a significant decrease of amyloid plaque load by partial clearance of pre-existing plaques and substantial prevention of de novo plaque formation. Efficacy of amyloid lowering was directly dependent on the ability of the antibody to cross the blood-brain-barrier and to bind to amyloid plaques. Remarkably, peripheral Aβ40 and Aβ42 levels were not increased after administration of the human antibody to PS2APP mice indicating that clearance of peripheral Aβ was not affected. The absence of stable antibody-Aβ complexes in blood may also have facilitated the pronounced and long lasting target occupancy observed in vivo in PS2APP mice. The fully human antibody described represents a novel, centrally-active anti-Aβ antibody with a broad and sensitive Aβ-amyloid specificity. Its binding mode and amyloid lowering capacity are promising features supporting further development as an immunotherapeutic treatment for Alzheimer's Disease.