The half-life of circulating antibodies is a measure of how long these antibodies remain in the blood after secretion from B cells (or after injection in the case of an administered antibody). The half-life is the mean time before the number of antibody molecules is reduced by half. Different antibody classes have different half-lives in circulation. IgE has a very short half-life of about 2 days in the circulation (although cell-bound IgE associated with the high-affinity IgE receptor on mast cells has a very long half-life). Circulating IgA has a half-life of about 3 days (although most IgA is produced at mucosal sites and is secreted directly into the lumen of the gut or airway) and circulating IgM has a half-life of about 4 days. In contrast, circulating IgG molecules have a half-life of about 21 to 28 days.
The long half-life of IgG is attributed to its ability to bind to a specific Fc receptor called the neonatal Fc receptor (FcRn), which is also involved in the transport of IgG from the maternal circulation across the placental barrier. FcRn structurally resembles MHC class I molecules. In pregnant females, it transports IgG molecules from the maternal blood, across the placenta, and into the fetal circulation, where it protects newborns from infections. FcRn is also found on endothelial cells, macrophages, and other cell types, and binds to IgG that is ingested by pinocytosis from the blood into endosomes (Fig. 1). FcRn has two distinct binding sites: one for the Fc portion of IgG and the other for serum albumin. The IgG (and albumin) remain bound to FcRn in the acidic environment of the endosomes. FcRn does not target the bound IgG or albumin to lysosomes (the usual fate of many ingested molecules) but recycles them to the cell surface and releases them in the neutral pH of the blood, returning the IgG and albumin to the circulation. This intracellular sequestration of IgG away from lysosomes prevents the IgG from being degraded as rapidly as most other plasma proteins, including other antibody classes, and, as a result, the IgG class has a relatively long half-life. A similar mechanism accounts for the extended half-life of plasma albumin. There are some differences in the half-lives of the four human IgG sub classes. IgG3 is relatively short lived because it binds less well to FcRn. IgG1 and IgG2 are the most long lived (and most efficient in terms of effector functions), and IgG4 is relatively long lived and can neutralize antigens but lacks other effector functions.
Fig1. FcRn (neonatal Fc receptor) contributes to the long half-life of immunoglobulin G (IgG) molecules. The FcRn is an IgG and albumin-binding receptor with separate binding sites for IgG and albumin. Micropinocytosed IgG (and albumin) molecules in endothelial cells bind FcRn in the acidic environment of endosomes. In endothelial cells, FcRn directs the IgG (and albumin) molecules away from lysosomal degradation and releases them when vesicles fuse with the cell surface, exposing FcRn-IgG and FcRn-albumin complexes to neutral pH.
The FcRn-mediated protection of IgG from catabolism has been exploited to provide a therapeutic advantage for certain injected proteins by producing fusion proteins containing the biologically active part of the protein and the Fc portion of IgG. The Fc portion enables the proteins to bind to the FcRn and thus extends the half-lives of the injected proteins. One therapeutically useful fusion protein is TNFR-Ig, which consists of the extracellular domain of the type II TNF receptor (TNFR) fused to an IgG Fc domain. This fusion protein binds to and blocks the inflammatory actions of TNF, similar to an anti-TNF antibody, and is used to treat certain immune disorders such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis (Fig. 2). Another fusion protein used therapeutically is CTLA-4-Ig, containing the extracellular domain of the CTLA-4 receptor fused to the Fc portion of human IgG. CTLA-4-Ig binds to and blocks B7 costimulators, which are required for T-cell activation, and it has been used in the treatment of rheumatoid arthritis and kidney transplant rejection.
Fig2. A monoclonal antibody and a cytokine receptor–immunoglobulin G (IgG) Fc fusion protein, both used therapeutically. An antibody specific for the cytokine tumor necrosis factor (TNF) (left) can bind to and block the activity of the cytokine. The extracellular domain of the TNF receptor (TNFR) (right) is also an antagonist of the cytokine and linking this soluble receptor domain to an IgG Fc domain (by recombinant DNA technology) increases the half-life of the receptor in the circulation.
A novel therapeutic has been developed that reduces the half-life of IgG without altering the half-life of serum albumin. It consists of the Fc portion of IgG engineered to bind more efficiently to FcRn than IgGs and to not block the region of FcRn that binds albumin (see Fig. 1). This therapeutic is approved for use in myasthenia gravis, an autoimmune disease caused by IgG autoantibodies against the acetylcholine receptor, and has also been used in other autoimmune disorders. Patients treated with this agent have reduced levels of all IgG antibodies in the blood, including the autoantibodies that cause disease.
