. Naturally occurring autoantibodies against beta-amyloid: investigating their role in transgenic animal and in vitro models of Alzheimer's disease. J Neurosci. 2011 Apr 13;31(15):5847-54. PubMed.

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  1. It is gratifying to see a consensus emerging about the existence of naturally occurring conformation-selective anti-amyloid antibodies in human plasma and intravenous immunoglobulin (IVIG). This publication by Dodel and colleagues adds to reports by O’Nuallain (2010), Szabo (2010), and others highlighting the properties and therapeutic potential of endogenous human antibodies that preferentially bind to oligomeric and fibrillar β amyloid aggregates rather than monomers.

    In interpreting the findings of Dodel and colleagues, it is important to keep in mind that there is more than one pool of conformation-selective anti-amyloid antibodies in the human repertoire. We recently reported the avidity constants (Kd) of various anti-amyloid antibodies found in human plasma and IVIG (Szabo et al., 2010). Using surface plasmon resonance and other techniques, we identified at least two pools of human anti-amyloid antibodies with distinguishing avidities: lower avidity antibodies with Kds in the micromolar range and higher avidity antibodies with Kds in the range of tens of nanomoles. A calculation from the sensograms in Fig 4E of Dodel et al. suggests that the anti-oligomer antibodies the authors extracted from a commercial IVIG product have a Kd in the micromolar range, consistent with the lower avidity pool. This subset of antibodies can be expected to bind to several auto-antigens in addition to β amyloid owing to inherent polyvalency. This could explain why the animal and cell culture studies reported by the authors required as much as 15 micromoles of antibody to obtain biological effects. Very high doses of IVIG would be required to achieve 15 micromolar concentrations of anti-oligomer antibodies in the CSF of Alzheimer’s patients. This is especially salient because the reported benefits of IVIG in Alzheimer’s patients followed an inverted dose response curve (Relkin et al., 2009), with higher doses showing less apparent efficacy.

    Future investigations should specify the avidities of the antibodies under study and employ doses that better reflect the natural abundance and/or the levels of antibodies achieved in patients after IVIG infusions. Despite this caveat, we wholeheartedly agree with the authors’ conclusion that naturally occurring conformation-selective human anti-amyloid antibodies hold considerable therapeutic promise for the treatment of Alzheimer’s disease. That is one of the principal reasons that we’ve carried out a number of clinical trials of IVIG for AD since 2004, including the Baxter/NIH co-sponsored multicenter Phase 3 study initiated in 2008 that is currently ongoing at 42 ADCS sites in the U.S. and Canada.

    References:

    . Anti-amyloidogenic activity of IgGs contained in normal plasma. J Clin Immunol. 2010 May;30 Suppl 1:S37-42. PubMed.

    . 18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiol Aging. 2009 Nov;30(11):1728-36. PubMed.

    . Measurement of anti-beta amyloid antibodies in human blood. J Neuroimmunol. 2010 Oct 8;227(1-2):167-74. PubMed.

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