IgG Dimers in Multidonor-Derived Immunoglobulins: Aspects of Generation and Function

Abstract

Immunoglobulin G (IgG) concentrates for therapeutic purposes, like passive immunotherapy, supplementation in inherited or acquired deficiencies or immunomodulation, are prepared from multidonor-derived plasma pools. They usually contain varying amounts of dimeric IgG. The essential factor influencing dimer formation is the pool size; in addition, molecular properties of IgG and a variety of production process- and formulation-specific parameters are important. Numerous experimental findings suggest that dimers are predominantly generated by interactions of idiotypic and anti-idiotypic antibodies (Ids, anti-Ids). Ab-inherent crossreactivity, frequency distribution of both the affinities for particular Id-anti-Id interactions and the corresponding dimer concentrations still have to be elucidated. All these parameters influencing molecular features and functional activity of IgG dimers hamper the assay-dependent measurement of biological efficacy and correlation of total IgG content. A more detailed understanding may help to better control the dual nature of dimer-dependent biological activity comprising both undesirable (e.g., hypotension) and desirable effects of dimeric IgG (blockade of the reticuloendothelial system, RES, in immune thrombocytopenic purpura, ITP). These effects are detectable in in vitro and in vivo models and are thought to be of relevance for humans.

Interactions between immunoglobulin G molecules

“…IgG dimers form with the participation of interaction sites that are located on the distal tips of Fab. The results obtained suggest that the dimerization is primarily due to the idiotype-anti-idiotype reaction of two IgG molecules which occurs when the anti-idiotypic combining site of one IgG molecule reacts with an idiotypic antigenic determinant of another IgG molecule [41,42]. Both interaction sites, idiotypic and anti-idiotypic, participating in the reaction are composed of the residues of V domains.…”

“…By Fab-Fab IgG dimers in immune globulins [4,5,41,42] IgG at high concentrations [8,9,13,14] By Fc-Fc In immune precipitates [16][17][18] IgG4 interactions [25,27] pFc -Fc interaction [29] In Fc crystals [32] could be found. In IG pools collected from 5000 donors, about 12% dimers were found; in pools from 10,000 donors 25% dimers were found, and in pools from 100,000 donors up to 40% dimers were found.…”

Naturally Occurring Antibodies/Autoantibodies in Polyclonal Immunoglobulin Concentrates

“…Immunoglobulin solutions, when stored, are forming an equilibrium between dimers monomers and probably oligomers. 74,75 Only a part of the dimer population is of the Id/anti-Id type. The other populations of dimers are most likely results of hydrophobic interactions of IgG molecules.…”

Polyreactive antibodies in multidonor-derived immunoglobulin G: Theory and conclusions drawn from experiments

“…That seems less likely the smaller the donor pool size is the md-IgG fraction has been prepared from. IgG of single donors contains only trace amounts of dimers (reviewed in Gronski 2006), which, to the knowledge of the authors, have not yet been characterized in detail; moreover, the experimental proof of their exclusive IgG origin and ability to non-covalently associate is also still missing.…”