Catalytic antibodies to amyloid β peptide in defense against Alzheimer disease

Abstract

Immunoglobulins (Igs) that bind amyloid β peptide (Aβ) are under clinical trials for immunotherapy of Alzheimer disease (AD). We have identified IgMs and recombinant Ig fragments that hydrolyze Aβ. Hydrolysis of peripheral Aβ by the IgMs may induce increased Aβ release from the brain. The catalytic IgMs are increased in AD patients, presumably reflecting a protective autoimmune response. Reduced Aβ aggregation and neurotoxicity attributable to the catalytic function were evident. These findings provide a foundation for development of catalytic Igs for AD immunotherapy. KeywordsCatalytic antibodies; proteolytic IgM; amyloid β peptide; Alzheimer's disease; immunotherapy Take-home messages• Human IgM autoantibodies hydrolyze Aβ via a serine protease-like mechanism. Brain and peripheral Aβ are in equilibrium with each other. Peripheral Aβ hydrolysis may induce depletion of the brain Aβ stores without IgM passage across the BBB.• Recombinant Ig fragments that hydrolyze Aβ have been isolated from human libraries. Theoretically, catalytic Igs that enter the brain are predicted to clear Aβ deposits without inducing inflammatory and microhemorrhage effects associated with conventional Igs.• Catalytic autoantibodies appear to represent a natural protective mechanism against AD. High activity catalytic Igs isolated from the human repertoire are candidates for for further consideration as immunotherapeutic agents. Immunotherapy of Alzheimer disease (AD)Approximately 26 million humans have AD worldwide. No truly effective therapy is available for AD treatment. Accumulation of amyloid β (Aβ) peptide aggregates is thought to play a crucial role in the neurodegenerative events underlying AD. 1 The Aβ aggregates are composed of 39-43 residue peptides generated by proteolytic processing of amyloid precursor protein (APP) by the β-and γ-secretases. The predominant product of this processing pathway is Catalytic autoantibodies to AβOur approach to developing immunotherapeutic reagents for AD is based on the expression of specific proteolytic activity by naturally occurring Igs. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptWe have reported the proteolytic activity of a panel of 10 monoclonal IgMs from patients with Waldenström's macroglobulinemia using model peptide substrates. 26 Two monoclonal IgMs from this panel also hydrolyzed Aβ40 and Aβ42. 27 Neither Aβ40-hydrolyzing IgM displayed binding of biotinylated Aβ40 in an ELISA test. Electrospray ionization-mass spectrometry (ESI-MS) of the product peptides generated by IgMs yielded mass values suggesting that Lys28-Gly29 is the major hydrolysis site and Lys16-Leu17, the minor hydrolysis site (Fig 1A). The catalytic activity of a monoclonal catalytic IgM was titrated using various concentrations of the electrophilic phosphonate diester. This yielded a value of 10.2 catalytic sites/IgM molecule, compared to the theoretical value of 10 antigen combining sites. 27 The catalytic activity was retained in the Fab fragments of the IgM and the activity ...

Proteolytic Degradation of Amyloid -Protein

“…Interestingly, Ab-degrading antibodies are present in the sera of normal subjects and, notably, are increased in AD patients (Paul et al 2010). Such antibodies can be harvested and may have therapeutic potential (Taguchi et al 2008a). The exciting potential of catalytic Ab-degrading antibodies makes this a topic worthy of continued investigation.…”

“…Catalytic antibodies have been suggested as an alternative that, by virtue of their higher specificity for particular antigenic targets, might improve the selectivity for Ab. A surprisingly large number of Abdegrading immunoglobulins (Igs) and Ig-fragments have been discovered or engineered (Taguchi et al 2008a). Although the catalytic efficiencies of most Ab-degrading antibodies is currently orders of magnitude slower than AbDPs, the technology exists to engineer existing antibodies or select new ones with improved properties (Taguchi et al 2008b).…”

Amyloid beta: structure, biology and structure-based therapeutic development

“…The hormone melatonin may be effective against amyloid by interacting with dimers of the soluble Aβ peptide and inhibiting their aggregation [293][294][295] . The cannabinoid HU-210 [296] has been shown to prevent Aβ-induced inflammation [297] .…”

Proteolytic activity of IgG-antibodies of mice, immunized by calf thymus histones

“…Вузька субстратна специфічність робить прот абзими перспективними молекулярними мар-керами у прогнозуванні розвитку автоімунних захворювань. Протеолітично активні антитіла було виявлено в сироватці крові хворих на деякі онкологічні та спадкові захворювання [10,11], a також у частини клінічно здорових людей [3,[12][13][14][15]. Показано, що в нормі протабзими мо-жуть бути залучені в руйнування і видалення з організму низки патогенних протеїнів, задіяних у розвитку вірусних інфекцій [3] і нейродегене-ративних захворювань [12][13][14][15].…”