Pooled Human Immunoglobulin Preparations as Immunomodulating Drugs

Abstract

It is time to celebrate the 125th anniversary of the first successful attempt to develop and use a specific high-titer antitoxic serum for treating diphtheria, a deadly infectious disease. This was followed by major advances in passive immunotherapy 75 years ago (production of pooled human IgG for subcutaneous injection) and 50 years ago (widespread technology for producing immunoglobulin preparations for intravenous administration). More than 200 tons of pooled human IgG are produced per year worldwide. The preparation is used primarily for IgG substitution in patients with primary and secondary immunodeficiencies, as well as for an immunomodulating treatment of a growing number of autoimmune and inflammatory diseases. These preparations contain the pooled IgG antibody repertoire of a large population of healthy plasma donors. This repertoire includes antibodies that neutralize pathogens and their factors of virulence, anti-idiotypic antibodies, and antibodies to other foreign and own proteins, as well as to carbohydrate antigens. Naturally polyspecific antibodies that are present in all healthy individuals play an important role as a first-line defense against bacteria and viruses. After exposure to protein-modifying agents, some IgG molecules can acquire the ability to bind novel structurally unrelated antigens. This phenomenon is referred to as induced polyspecificity. The list of these protein-modifying molecules was shown to include low-pH buffers, free heme, pro-oxidative ferrous ions, reactive oxygen species, etc. Such modified antibody preparations may have a therapeutic potential, since their administration to animals with experimental sepsis or aseptic systemic response syndromes significantly improved survival rates, while the same dose of the native preparation had no effect. We also hypothesize that the aggressive protein-modifying molecules released in sites of inflammation and tissue damage could also modify the antigen-binding behavior of surface immunoglobulin B cell receptors and the structurally related T cell receptors. This “specificity editing” of both types of receptors may play a major role in the body’s defense mechanisms.