Abstract
Recent phase II and III studies with intravenous immunoglobulin (IVIG) in patients with Alzheimer’s disease (AD) did not find evidence for the slowing of AD progression compared to placebo-treated patients, in contrast to encouraging results in pilot studies. An additional phase III trial is ongoing. If negative results are found, then further AD studies with IVIG are unlikely unless a manufacturer opts for a trial with high-dose IVIG, which would increase its anti-inflammatory effects but also the risk for adverse events. An alternative approach could be an AD-specific IVIG, supplementing IVIG with higher concentrations of selected antibodies purified from it or produced via recombinant polyclonal antibody technology. These antibodies could include those to amyloid-beta (Aβ, tau protein, inflammatory cytokines, complement activation proteins, and the receptor for advanced glycation end products. IgG fragment crystallizable (Fc) fragments containing terminal sialic acid could be added to increase anti-inflammatory effects. While this product might be more effective in slowing AD clinical progression than current IVIG, there are difficulties with this approach. Preclinical studies would be required to determine which of the antibodies of interest for supplementing current IVIG (for example, antibodies to phosphorylated or oligomeric tau) are actually present (and, therefore, available for purification) in IVIG, and the effects of the product in mouse models of AD. An Investigational New Drug application for an AD-specific IVIG would require United States Food and Drug Administration approval. If the drug would be found to benefit AD patients, meeting the increased demand for IVIG would be challenging.
Highlights
5.2 million Americans are currently diagnosed with Alzheimer’s disease (AD)
Since the amyloid cascade hypothesis was published in 1991 [4], AD therapy has focused primarily on amyloid-beta
Of relevance is a recent study [65] in which repeated administration of monoclonal sequence-independent antioligomer antibodies to 3xTg-AD mice resulted in improved cognitive performance, reduced hippocampal plaques and brain levels of soluble and insoluble Aβ40 and Aβ42, and reduced microglial activation
Summary
5.2 million Americans are currently diagnosed with Alzheimer’s disease (AD). Of relevance is a recent study [65] in which repeated administration of monoclonal sequence-independent antioligomer antibodies to 3xTg-AD mice resulted in improved cognitive performance, reduced hippocampal plaques and brain levels of soluble and insoluble Aβ40 and Aβ42, and reduced microglial activation This treatment reduced tau hyperphosphorylation in hippocampal CA1 neurons, providing additional evidence for a relationship between AD’s Aβ and tau pathology [66,67,68]. The possibility is not ruled out that if the levels of these antibodies are increased in AD-specific IVIG, the resulting preparation could induce an autoimmune response Such an outcome has not been reported following IVIG treatment, Rosenmann et al [147] found that vaccination of C57BL/6 mice with full-length human tau induced anti-tau antibodies which were associated with development of tau pathology and encephalitogenicity (manifested by neurologic deficits).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
