Immunological Origin and Functional Properties of Catalytic Autoantibodies to Amyloid β Peptide

Department of Pathology and Laboratory Medicine, Chemical Immunology Research Center, University of Texas-Houston Medical School, Houston, TX 77030, USA.
Journal of Clinical Immunology (Impact Factor: 2.65). 05/2010; 30 Suppl 1(S1):S43-9. DOI: 10.1007/s10875-010-9414-5
Source: PubMed

ABSTRACT OBJECTIVES: 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 (Abeta) and to (2) evaluate the prospect of developing a catalytic IVIG (CIVIG) formulation for therapy of Alzheimer's disease (AD). CONCLUSIONS: Polyclonal autoantibodies from humans without dementia hydrolyzed Abeta 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 Abeta overexpression, which suggests a beneficial function of the catalytic activity. The catalytic autoantibodies impeded Abeta aggregation, dissolved preformed Abeta aggregates, and inhibited Abeta cytotoxicity in tissue culture. Recombinant catalytic antibodies from a human library have been identified, validating the phenomenon of antibody-catalyzed Abeta cleavage. As a single catalyst molecule inactivates multiple Abeta molecules, catalytic antibodies may clear Abeta efficiently. IVIG did not cleave Abeta, indicating the importance of purification procedures that maintain catalytic site integrity. Traditional Abeta-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 Abeta-specific catalytic subsets present in IgM and IgG from human blood.

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    ABSTRACT: Alzheimer’s disease (AD) is the most common dementia in the industrialized world with prevalence rates far over 30% in the over 80 years old population. The dementia causes enormous cost to the social health care systems besides the personal tragedies for the patients, families and caregivers. One of the pathological protein aggregations that occur in AD is the Amyloid-beta (Aβ) aggregation in extracellular plaques, accompanied by Tau hyperphosphorylation, chronic neuroinflammation and oxidative stress, leading to severe neurodegeneration of brain areas involved in learning and memory. Plaques, thus Aβ, appeared to be the more druggable and promising target for disease-modifying therapeutic strategies like passive immunotherapy with monoclonal antibodies (mAbs) against Aβ, though today it is clear that Aβ is a dreadful target. Meanwhile, the first-in-class mAb Bapineuzumab and the fast-follower mAb Solanezumab failed in Phase III whereas several other candidates – some of them modified 2nd generation mAbs – now entered Phase I (PF-05236812, BAN2401, SAR228810 and BIIB037) and Phase II (Gantenerumab and Crenezumab) respectively. Others are known to be in preclinical stages. On the first view, the above-cited mAbs cleared or improved amyloid burden and validated the proposed Aβ read-out biomarkers, but have yet not shown relevant improvement in the major aim in AD therapy: cognition. Also, currently under Phase III investigation, are human IgG from healthy donors. The latest, so-called IVIG, are nowadays interestingly reported to stabilize cognition in AD patients. In this review we discuss the immunological basis for the mechanism of action of passive Aβ immunotherapy, anti-Aβ mAbs and scaffolds in the pipelines and patents, their preclinical and clinical outcome and strategies for 2nd generation biobetters.
    Frontiers in Clinical Drug Research – Alzheimer Disorders. VOLUME: 1, Edited by Atta-ur-Rahman, 01/2013: pages 3 - 85; Bentham Science., ISBN: 978-1-60805-723-8
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    ABSTRACT: Like infectious disease vaccines, effective Alzheimer's disease vaccines should elicit an antibody response similar to the natural autoantibodies found in serum and preparations of intravenous immunoglobulins, which recognize an array of amyloid-β conformations. An immune response that is the result of a progressive formation over time of antibodies against toxic amyloid-β conformations and that different from most vaccines under development, would require the whole protein as an antigen, including both B and T-cell epitopes. However, due to the presence of amyloid-β T-cell epitopes and the fact that such a protein is a Th1 immune modulator, safe and effective vaccines, besides eliciting Th2 immunity, should inhibit but not abolish Th1 immunity, which is needed for protection against pathogens; a strategy that would apply to other potential Alzheimer's disease vaccine antigens, e.g. tau. Due to immunosenescence, these vaccines would be more effective for preventive rather than therapeutic purposes, as younger individuals produce a better immune response. Recently developed novel adjuvants that most probably act at the dendritic cell level and that can deliver such a selective Th2 immune modulation while inhibiting Th1 immunity, would be crucial for the development of these proposed vaccines. protein, where the whole protein or some of its peptides with Th1 adjuvants may trigger a damaging inflammatory response [16,17]. Hence, there is a need to reassess the current AD vaccine paradigm and consider new approaches to its development. Different from infectious disease vaccines where the number of Th1 adjuvants is large, vaccines against neurodegenerative proteinopathies, like AD, have a negligible selection of adjuvants that stimulate solely Th2 immunity, alum being the most common [18]. Still, that alum does not elicit an effective immunity in the elderly, as shown by the age-associated decrease in the efficacy of the flu and other vaccines [19] and have cumulative neurotoxicity [20], would preclude its use in AD vaccines. That certain bacterial toxins are "conditional" Th2 adjuvants, i.e. the stimulated immunity would depend on the age and mode of administration among other factors, adds an element of risk when used in large populations; for example, cholera toxin elicits Th2 immunity in young animals, but induces Th1 immunity in older ones [21], as well as a Th17 immune response [22]. The recent reports that some well-defined helminth glycans and plant-derived glycosides elicit Th2-only immunity [18,23], despite the absence or presence of T-cell epitopes, offer a new approach to develop safe and effective AD vaccines. Access to adjuvants that stimulate Th2 but inhibit Th1 immunity would allow the use of whole proteins, e.g. Aβ 42 and tau; antigens that are not used because of the damaging inflammatory immune response caused by their T-cell epitopes. Significantly, since Aβ 42 has an intrinsic Th1 immune modulatory activity [24,25], the use of adjuvants that inhibit Th1 immunity will be essential with this antigen.
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    ABSTRACT: Alzheimer's disease (AD) is a devastating neurodegenerative form of dementia with increasing incidence rates in most countries. AD is characterized by amyloid plaques and neurofibrillary tangles in the brains of AD individuals accompanied by global neuronal loss. The peptide amyloid-β (Aβ) aggregates to amyloid plaques in AD brains. As a result, many therapeutic approaches target Aβ. Human plasma and the plasma product intravenous immunoglobulin (IVIG) contain naturally-occurring anti-Aβ antibodies (Nabs-Aβ) that appear to reduce risks of developing AD. IVIG sequesters Aβ and thus interferes with AD progression. This study reviews the role of different Aβ species, Nabs-Aβ, preclinical data, and clinical studies of IVIG as potential AD treatments. The focus of this study is the outcomes of a recent Gammaglobulin Alzheimer's Partnership Phase III trial that did not reach primary endpoints, as well as efforts to compare IVIG with current anti-Aβ monoclonals such as bapineuzumab, solanezumab, and BIIB037. Moreover, this study critically examines current market and ethical consequences of potential off-label uses of IVIG, limits in IVIG supply, and subsequent challenges.
    09/2014; 4:121-30. DOI:10.2147/DNND.S51786

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