Chapter 4: Multitasking by exploitation of intracellular transport functions the many faces of FcRn.

The MHC Class I-related receptor, FcRn, transports antibodies of the immunoglobulin G (IgG) class within and across a diverse array of different cell types. Through this transport, FcRn serves multiple roles throughout adult life that extend well beyond its earlier defined function of transcytosing IgGs from mother to offspring. These roles include the maintenance of IgG levels and the delivery of antigen in the form of immune complexes to degradative compartments within cells. Recent studies have led to significant advances in knowledge of the intracellular trafficking of FcRn and (engineered) IgGs at both the molecular and cellular levels. The engineering of FcRn-IgG (or Fc) interactions to generate antibodies of increased longevity represents an area of active interest, particularly in the light of the expanding use of antibodies in therapy. The strict pH dependence of FcRn-IgG interactions, with binding at pH 6 that becomes essentially undetectable as near neutral pH is approached, is essential for efficient transport. The requirement for retention of low affinity at near neutral pH increases the complexity of engineering antibodies for increased half-life. Conversely, engineered IgGs that have gained significant binding for FcRn at this pH can be potent inhibitors of FcRn that lower endogenous IgG levels and have multiple potential uses as therapeutics. In addition, molecular studies of FcRn-IgG interactions indicate that mice have limitations as preclinical models for FcRn function, primarily due to cross-species differences in FcRn-binding specificity.