Catalytic antibodies to amyloid β peptide in defense against Alzheimer disease

Chemical Immunology Research Center, University of Texas Houston Medical School, Houston, TX 77030, USA.
Autoimmunity Reviews (Impact Factor: 7.1). 06/2008; 7(5):391-7. DOI: 10.1016/j.autrev.2008.03.004
Source: PubMed

ABSTRACT Immunoglobulins (Igs) that bind amyloid beta peptide (Abeta) are under clinical trials for immunotherapy of Alzheimer disease (AD). We have identified IgMs and recombinant Ig fragments that hydrolyze Abeta. Hydrolysis of peripheral Abeta by the IgMs may induce increased Abeta release from the brain. The catalytic IgMs are increased in AD patients, presumably reflecting a protective autoimmune response. Reduced Abeta aggregation and neurotoxicity attributable to the catalytic function were evident. These findings provide a foundation for development of catalytic Igs for AD immunotherapy.

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    ABSTRACT: Abstract: Specific entities of naturally-occurring DNA hydrolytic/cytotoxic antibodies (abzymes) are linked to autoimmune and lymphoproliferative disorders. Suggested sequence of underlying activities conform to such entities penetrating the living cells, trans-locating to nucleus and recognising specific binding sites within single- or double-stranded DNA. Their origin is unknown since corresponding immunogens are unidentified. These anti-DNA antibodies could be the organism’s immune response to microbial attack. Their structure, function and pathogenicity were investigated in wet-lab and via bioinformatics in context of Rational Vaccine Designs. This paper offers a comprehensive critical review on the subject in the light of known and newly proposed concepts. Keywords: autoimmune diseases; human immunodeficiency virus; anti-DNA antibodies; DNA vaccine; RVD; rational vaccine design.
    Edited by Neelakanta P, Pavlovic M, Zhuang H, 02/2013: chapter From Pauling’s Abzyme Concept to the New era of Hydrolytic Anti-DNA autoatnibodies: A link to the rational vaccine design?: pages 220-238(18); , ISBN: Special Issue of IJBRA
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    Autoimmune Disorders - Pathogenetic Aspects, 10/2011; , ISBN: 978-953-307-643-0
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    ABSTRACT: Cell surface sialylation is known to be tightly connected with tumorigenicity, invasiveness, metastatic potential, clearance of aged cells, while the sialylation of IgG molecules determines their anti-inflammatory properties. Four sialidases - hydrolytic enzymes responsible for cleavage of sialic residues - were described in different cellular compartments. However, sialidases activity in body fluids, and specifically in blood serum, remains poorly studied. Here, we characterize first known IgG antibodies possessing sialidase-like activity in blood serum of multiple myeloma (MM) patients. Ig fractions were precipitated with ammonium sulfate (50% of saturation) from blood serum of 12 healthy donors and 14 MM patients, and screened for the presence of sialidase activity by using 4-MUNA (2'-(4-methylumbelliferyl)-α-D-N-acetylneuraminic acid) as substrate. High level of sialidase activity was detected in the MM patients, but not in healthy donors. Subsequent antibody purification by protein-G affinity chromatography and HPLC size exclusion chromatography at acidic conditions demonstrated that sialidase activity was attributable to IgG molecules. Sialidase activity was also specific for (Fab)(2) fragment of IgG and blocked by sialidase inhibitor DANA. Sialidase activity of IgG molecule was also confirmed by in gel assay for cleavage of sialidase substrate. Kinetic parameters of the catalysis reaction were described by Michaelis-Menten equation with K(m)  = 44.4-108 µM and k(cat) = 2.7-23.1 min(-1). The action of IgG possessing sialidase-like activity towards human red blood cells resulted in a subsequent increase in their agglutination by the peanut agglutinin, that confirms their desialylation by the studied IgG. This is the first demonstration of the intrinsic sialidase activity of IgG isolated from blood serum of MM patients.
    Journal of Molecular Recognition 07/2011; 24(4):576-84. DOI:10.1002/jmr.1071 · 2.34 Impact Factor