The neonatal Fc receptor, known as FcRn, is a specialized protein found on the surface of various cells throughout the body. Its designation as “neonatal” stems from its initial recognition for its involvement in transferring protective immunity from a mother to her offspring. This receptor plays a dual role: transporting maternal antibodies to a fetus or newborn, and recycling specific proteins in the bloodstream to prolong their presence in adults.
Maternal Antibody Transfer
FcRn provides passive immunity to infants. During pregnancy, this receptor facilitates the movement of Immunoglobulin G (IgG) antibodies from the mother’s bloodstream across the placenta to the developing fetus. This process begins around the second trimester and increases significantly in the third, ensuring the baby receives a robust defense against infections the mother has encountered. Placental syncytiotrophoblast cells express FcRn, allowing IgG molecules to bind to the receptor.
After birth, FcRn continues its protective role by transporting maternal IgG from ingested colostrum and milk. This transfer occurs as the antibodies cross the newborn’s intestinal cells and enter their bloodstream. The mechanism involves the receptor binding to IgG in an acidic environment (pH 6.0-6.5) inside cellular compartments called endosomes. This acidic pH promotes a strong interaction between FcRn and IgG.
Once the FcRn-IgG complex forms, it is transported across the cell, a process known as transcytosis. Upon reaching the opposite side of the cell, where the environment is more neutral (around pH 7.4), the receptor releases the IgG into the bloodstream. This pH-dependent binding and release mechanism moves these protective antibodies from the mother to the baby, providing temporary immunity during the early months of life.
Maintaining Antibody Levels in Adults
Beyond its role in newborns, FcRn performs a continuous function in adults by recycling specific proteins. In adults, FcRn rescues IgG antibodies and albumin, an abundant blood protein, from degradation. Cells throughout the body constantly take in fluids from the bloodstream through pinocytosis. Without FcRn, internalized IgG and albumin would be broken down within lysosomes, which are cellular waste disposal units.
FcRn acts as a salvage mechanism, preventing this degradation. When IgG and albumin enter the acidic environment of cellular endosomes, they bind to FcRn with high affinity. This binding diverts the proteins away from the lysosomal degradation pathway. The FcRn-bound proteins are then transported back to the cell surface and released into the neutral pH of the bloodstream, where binding affinity weakens, allowing their dissociation. This recycling process extends the lifespan of IgG antibodies (around 21 days for IgG1, IgG2, and IgG4) and albumin (about 20 days).
A Target for Autoimmune Disease Treatment
The FcRn receptor is an important target for treating autoimmune diseases by blocking its function. In many autoimmune conditions, the body mistakenly produces harmful autoantibodies, often of the IgG class, which attack its own tissues. While FcRn’s normal recycling pathway maintains beneficial IgG levels, it also prolongs the presence of these harmful autoantibodies.
Administering specific drugs called FcRn inhibitors disrupts the recycling pathway for all IgG antibodies. These inhibitors, such as efgartigimod, bind to FcRn, preventing it from interacting with IgG. As a result, both normal IgG and pathogenic autoantibodies are no longer rescued from degradation and are broken down faster. This accelerated breakdown reduces overall IgG levels, including harmful autoantibodies, in the bloodstream.
Lowering the concentration of these autoantibodies can significantly reduce the symptoms and progression of autoimmune diseases. For instance, efgartigimod is approved for treating generalized myasthenia gravis (gMG), a condition characterized by autoantibodies that impair nerve-muscle communication. FcRn inhibitors are also used or investigated for chronic inflammatory demyelinating polyneuropathy (CIDP), where autoantibodies damage nerve myelin, and other IgG-mediated autoimmune disorders like rheumatoid arthritis and systemic lupus erythematosus.
Extending the Life of Therapeutic Drugs
In a contrasting therapeutic strategy, scientists can harness the FcRn pathway to extend the lifespan of beneficial therapeutic drugs. Many modern medicines, particularly those developed through biotechnology, are therapeutic antibodies designed to target specific disease pathways, such as those used in cancer or arthritis treatment. These therapeutic antibodies are IgG molecules. By modifying these drug molecules, researchers can enhance their interaction with the FcRn receptor.
This engineering often involves making specific amino acid changes in the Fc region of the therapeutic antibody. These modifications increase the drug’s binding affinity to FcRn, particularly in the acidic environment of the endosome. When the engineered therapeutic antibody binds more effectively to FcRn, it utilizes the body’s natural recycling system more efficiently.
Stronger and more prolonged binding to FcRn means the therapeutic antibody is rescued from degradation more frequently and returned to circulation. This leads to an extended half-life for the drug in the bloodstream, allowing it to remain active for longer periods. A direct benefit for patients is the potential for less frequent dosing or injections, improving convenience and adherence to treatment. For example, ravulizumab, an approved therapeutic antibody, was engineered with FcRn-binding modifications, enabling a much longer dosing interval compared to its predecessor.