Should development of Alzheimer's disease-specific intravenous immunoglobulin be considered?

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.