S1-02-02: Natural human antibodies targeting amyloid aggregates in intravenous immunoglobulin

Abstract

Intravenous Immunoglobulin (IGIV) is unique among immunotherapy agents under study for treatment of Alzheimer's disease (AD) because it contains natural human antibodies against β-amyloid (Aβ). Three studies to date have shown that administration of IGIV results in cognitive improvements in AD patients and significant lowering of Aβ levels in cerebrospinal fluid (CSF). It was originally proposed that IGIV exerts its Aβ-lowering effects through antibodies against linear epitopes of the Aβ monomer. However, titers of sequence-specific anti-Aβ antibodies in IGIV are inadequate to explain its anti-amyloid effects in vivo. We recently identified a new group of antibodies in IGIV, plasma and CSF that we refer to as “Conformational Human Antibodies to Misfolded Proteins” (CHAMP). We studied whether actions of these antibodies can explain the therapeutic effects of IGIV in AD patients. Synthetic Aβ preparations containing purified monomers, oligomers and fibrils were created in accordance with published protocols. Complexes of IGIV and soluble Aβ aggregates were isolated by Size Exclusion Chromatography. IGIV's effects on Aβ assembly were studied using Thioflavin T fluorescence and Transmission Electron Microscopy. Dot blots and ELISA techniques were used to quantify levels of CHAMP in IGIV, plasma and CSF. IGIV binds with high affinity to aggregated forms of Aβ but not to the native Aβ monomer. This selectivity appears to be the result of CHAMP binding to conformational neo-epitopes within Aβ oligomers and fibrils. Decreases in free Aβ brought about by IGIV can be explained by CHAMP-induced alterations in the equilibrium between Aβ monomers, oligomers and fibrils. Infusion of IGIV significantly increases titers of CHAMP in the plasma and CSF of AD patients. CHAMP, a novel group of human antibodies within IGIV and human blood, binds to aggregated forms of Aβ and other amyloid-forming proteins but not to monomers. CHAMP exerts a dose-dependent effect on Aβ aggregation that parallels the inverted U-shaped dose-response curve associated with IGIV treatment in AD studies. Further studies should help to establish whether CHAMP constitutes an innate immunologic defense against disorders of protein folding as well as the basis for IGIV's therapeutic benefits in AD.