期刊
JOURNAL OF CLINICAL IMMUNOLOGY
卷 30, 期 -, 页码 S43-S49出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s10875-010-9414-5
关键词
Catalytic antibody; amyloid beta peptide; Alzheimer's disease; immunotherapy
类别
资金
- US National Institutes of Health [1R01AG025304]
Objectives The objectives of this study are to (1) evaluate the ability of the immune system to synthesize specific antibodies that catalyze the degradation of amyloid beta peptide (A beta) and to (2) evaluate the prospect of developing a catalytic IVIG (CIVIG) formulation for therapy of Alzheimer's disease (AD). Polyclonal autoantibodies from humans without dementia hydrolyzed A beta specifically. The catalytic activity improved as a function of age. Patients with AD produced catalytic antibodies at increased levels. IgM-class antibodies expressed the activity at levels superior to IgGs. Production of catalytic autoantibodies appears to be an innate immunity function with adaptive improvements occurring upon A beta overexpression, which suggests a beneficial function of the catalytic activity. The catalytic autoantibodies impeded A beta aggregation, dissolved preformed A beta aggregates, and inhibited A beta cytotoxicity in tissue culture. Recombinant catalytic antibodies from a human library have been identified, validating the phenomenon of antibody-catalyzed A beta cleavage. As a single catalyst molecule inactivates multiple A beta molecules, catalytic antibodies may clear A beta efficiently. IVIG did not cleave A beta, indicating the importance of purification procedures that maintain catalytic site integrity. Traditional A beta-binding antibodies form immune complexes that can induce inflammatory reaction and vascular dysfunction. Catalysts do not form stable immune complexes, minimizing these risks. Criteria appropriate for developing a CIVIG formulation with potential therapeutic utility are discussed, including isolation of the A beta-specific catalytic subsets present in IgM and IgG from human blood.
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