Firstly, let us learn some antibodies:
Anti-Human FcRn Antibody
The FcRn-specific human antibody targets FcRn which is a receptor with a high affinity for IgG. The binding of the antibody to FcRn can reduce serum pathogenic auto-antibody levels, and therefore the FcRn antibody can be used to treat autoimmune diseases such as immune neutropenia, Guillain-Barre syndrome, epilepsy, autoimmune encephalitis, Isaac’s syndrome, nevus syndrome, pemphigus vulgaris and so on.
Recombinant Human monoclonal antibody expressed in CHO binds to Human FcRn. HL161 is a novel anti-FcRn antibody that can be used as a new therapeutic option for pathogenic IgG-mediated autoimmune diseases.
What is FcRn?
Figure1. FcRn transmits maternal antibodies to the fetus
Immunoglobulin G (IgG) is the most abundant immunoglobulin component in colostrum. Both maternal IgG secretion to breast and uptake by newborn animals need to cross the epithelial cell barrier through cell transfer. This process requires the participation of a receptor with transport function, namely neonatal Fc receptor (FcRn). FcRn was first found in rodents transporting maternal IgGs to newborns in the intestine. With the deepening of research, more data show that FcRn not only transports IgGs through the placental barrier during pregnancy, but also maintains the serum IgG level, which plays an important role in many organs and tissues.
Molecular structure of FcRn
FcRn is a heterodimer consisting of two subunits, large subunit with molecular weight ranging from 45 kD to 53 kD called alpha chain. Small subunit is beta-2 microglobulin with molecular weight of 14 kD, called beta chain. The two chains are bound together in the form of non-covalent bonds. Beta-2 microglobulin plays an important role in the function of FcRn. Alpha chain must be assembled with beta-2 microglobulin before it can be put into operation. Like MHC-I, the alpha chain has three extracellular functional regions, one transmembrane region and one tail region. The homology of transmembrane region, extracellular functional region and MHC class I molecule is high, but the homology of cytoplasmic tail region is low. The tail region of cytoplasm consisting of 44 amino acid residues may contain signals that mediate intracellular pathways. The bovine cytoplasmic tail region is the shortest found so far among all kinds of animals. In addition, ruminant FcRn alpha chain amino acids are highly similar to human newborn Fc receptor (hFcRn).
Function of FcRn
- The role of FcRn in placenta
Ruminant maternal IgG transports through mammary gland epithelium and small intestinal epithelium. Colostrum and normal breast are the main sources of IgG, which are mainly transported to the fetus through maternal-fetal barrier or yolk sac in primates and rodents. In humans, FcRn is expressed in the vesicles in the syncytiotrophoblast. The syncytiotrophoblast contacts with maternal blood and sinks into the endosomes, then the IgG and FcRn bind tightly during the acidification of the endosomes. The vesicles move to the syncytiotrophoblast and the fetus surface fuses with the membrane. IgG is separated from FcRn at physiological pH. FcRn passes through trophoblast cells and returns to the mother, transporting more IgG to the fetus.
- The role of FcRn in blood circulation
FcRn can prolong half-life of IgG in serum, maintaining high level of antibody concentration in blood circulation and dynamic balance. FcRn was expressed in human, pig and bovine vascular endothelium. Many experiments have proved that vascular endothelium is an important part of FcRn to protect IgG from metabolism. FcRn not only absorbs IgG from extracellular acidic environment, but also participates in the steady-state regulation of circulating IgG level in endothelial cells.
- The role of FcRn in intestinal tract
The expression pattern of FcRn in human intestine is significantly different from that in rodents. FcRn is expressed in human fetal and adult intestinal epithelial cells. However, FcRn was less expressed in the intestine of adult rodents, and the highest expression was found in proximal intestinal epithelial cells in neonatal period, which declined rapidly after weaning. In addition to regulating serum IgG levels and transporting maternal IgGs, FcRn transport may have other significance: oral IgG may be transported through FcRn for passive immunization; by analogy with dairy cows, FcRn transports IgG to the intestine may play a role in eliminating IgGs.
- The role of FcRn in breast
FcRn is expressed in mammary glands of many animals such as pigs, rodents, ruminants and humans. FcRn of breast directly combines with Fc fragment of IgG to transport IgG, which is involved in maintaining the dynamic balance of IgG.
Influencing factors of FcRn expression
- The effect of hormones on FcRn
Hormones affect the transport of IgG and the expression of IgG in FcRn. In mammary gland, FcRn participates in the secretion of IgG1 and is affected by hormone regulation. Prolactin regulates the activity of IgGl and IgG2 transport receptors. Prolactin can inhibit the transport of IgG to breast and reduce the expression of IgG binding protein in mammary epithelial cells. Exogenous corticosteroids and thyroid hormones affect immunoglobulin transport and FcRn expression in a dose-and time-dependent manner.
- The effect of different physiological stages on FcRn
The expression of FcRn varies in different physiological stages. In rodents and human placentas, FcRn transports IgG to the fetus through the epithelial cell barrier. The expression of FcRn was almost not detected in intestinal epithelial cells of rodents after weaning, and IgG was not absorbed by adult animals after oral administration. Adult intestinal epithelial cells still express FcRn. FcRn was detected in cultured epithelial cells in vitro, and it can transport IgG bi-directionally across monolayer cells.
- The effect of gene polymorphism on FcRn
Gene polymorphism affects the expression of FcRn, even in different individuals and corresponding parts of the same species.
FcRn is expressed in many tissues and organs such as human, cattle, sheep, pigs, rats and mice. The function is also influenced by hormones, physiological stages and gene polymorphisms. In view of the basic role of FcRn in IgG metabolism, the application value of FcRn can be realized through the following ways: (1) FcRn binds to immunoglobulin, saturates FcRn by intravenous injection of immunoglobulin or specific antibody in order to shorten the half-life of pathogenic IgGs in autoimmunity and reduce the pathological response; The IgGFc region of n-interaction prolongs the half-life of therapeutic antibodies and enhances the immune function of the body. (2) Studying the metabolism of IgG in animals can serve the production of polyclonal antibodies. At present, human polyclonal antibodies are widely used in treatment, but their sources are limited. If IgG is selectively transported from serum to milk, it can not only reduce the production cost of immunoglobulin, but also improve the safety of the product, making it possible to produce large-scale therapeutic antibodies. (3) The study of FcRn gene polymorphism has broad prospects. The haplotypes of dairy cows can affect the acquisition of maternal antibodies, thus affecting the morbidity and mortality of calves. Through genetic improvement, cattle screening can enhance the passive immunity of calves and improve the economic benefits of animal husbandry production. In addition, gene polymorphism can cause specific pharmacological and toxicological effects in different individuals after taking drugs, resulting in differences in drug treatment effect, providing a scientific basis for clinical drug treatment.