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P3‐420: A novel recombinant human amyloid plaque‐specific antibody for the treatment of Alzheimer's disease: Molecular properties and preclinical efficacy
Author(s) -
Bohrmann Bernd,
Benz Joerg,
Baumann Karlheinz,
Huber Walter,
Knoflach Fred,
Messer Juerg,
Oroszlan Krisztina,
Ozmen Laurence,
Richter Wolfgang,
Nordstedt Christer,
Loetscher Hansruedi
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.1963
Subject(s) - in vivo , antibody , epitope , monoclonal antibody , chemistry , in vitro , recombinant dna , amyloid (mycology) , epitope mapping , fibril , biochemistry , microbiology and biotechnology , medicine , biology , immunology , inorganic chemistry , gene
Background: Preclinical profile of Ab binding properties and efficacy of a fully human monoclonal anti-Ab antibody. Methods: Binding properties were assessed by Biacore and X-ray crystallography. In life efficacy for plaque binding and Ab clearance was characterized by immunoassays and quantitative image analysis. Results: Anti Ab 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 Ab40/42. Epitope mapping with linear Ab decapeptides showed reactivity against N-terminal (EFRHDSGYE) and central (FFAEDVGS) amino acids, suggesting recognition of a unique structure present on Ab fibrils. X-ray crystallography revealed an interesting binding mode involving multiple amino acids of heavy and light chain CDRs and all residues of Ab 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 Ab40 and Ab42 levels were not increased after administration of the human antibody to PS2APP mice indicating that clearance of peripheral Ab was not affected. The absence of stable antibody-Ab complexes in blood may also have facilitated the pronounced and long lasting target occupancy observed in vivo in PS2APP mice. Conclusions: The fully human antibody described represents a novel, centrally-active anti-Ab antibody with a broad and sensitive Ab-amyloid specificity. Its binding mode and amyloid lowering capacity are promising features supporting further development as an immunotherapeutic treatment for Alzheimer’s Disease.