All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Albumin is a multifunctional transporter of different endogenous as well as exogenous compounds, such as ions, fatty acids, amino acids, hemin, bilirubin and various drugs (Peters, T. Jr. Serum albumin. Adv. Protein Chem. 37, 161-245 (1985)). It is the most abundant protein in blood and thus contributes to maintaining the osmotic pressure. The high serum concentration of albumin is due to the rate of synthesis that takes place in the liver and its interaction with the neonatal Fc receptor, abbreviated FcRn (Chaudhury, C. et al.). The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan. J. Exp. Med. 197, 315-322 (2003); Anderson, C. L. et al. Perspective-FcRn transports albumin: relevance to immunology and medicine. Trends Immunol. 27, 343-348 (2006). FcRn is a dual binding receptor that, in addition to albumin, binds IgG, and protects both proteins from intracellular degradation and thus plays a key role in prolonging the half-lives of these proteins (Anderson, C. L. et al. Perspective-FcRn transports albumin: relevance to immunology and medicine. Trends Immunol. 27, 343-348 (2006); Roopenian, D. C. & Akilesh, S. FcRn: the neonatal Fc receptor comes of age. Nat. Rev. Immunol. 7, 715-725 (2007); Ward, E. S. & Ober, R. J. Chapter 4: Multitasking by exploitation of intracellular transport functions the many faces of FcRn. Adv. Immunol. 103, 77-115 (2009).
FcRn is a nonclassical major histocompatibility (MHC) class I molecule that consists of a unique transmembrane heavy chain (HC) that is non-covalently associated with the common 02-microglobulin (β2m). Crystal structures of FcRn show the extracellular part of the HC with an amino-terminal α1-α2 platform of eight antiparallel β-pleated strands topped by two long α-helices followed by the membrane proximal α3-domain (Burmeister, W. P., Huber, A. H. & Bjorkman, P. J. Crystal structure of the complex of rat neonatal Fc receptor with Fc. Nature 372, 379-383 (1994), Burmeister, W. P., Gastinel, L. N., Simister, N. E., Blum, M. L. & Bjorkman, P. J. Crystal structure at 2.2 A resolution of the MHC-related neonatal Fc receptor. Nature 372, 336-343 (1994); West, A. P. Jr. & Bjorkman, P. J. Crystal structure and immunoglobulin G binding properties of the human major histocompatibility complex-related Fc receptor. Biochemistry 39, 9698-9708 (2000)). The 132m unit is tightly bound to residues located below the α1-α2 platform and to the α3-domain. Classical MHC class I molecules bind to short peptides in their peptide-binding groove, located between the two α-helices on the α1-α2 platform but this groove is occluded and empty in FcRn (Burmeister, W. P., Gastinel, L. N., Simister, N. E., Blum, M. L. & Bjorkman, P. J. Crystal structure at 2.2 A resolution of the MHC-related neonatal Fc receptor. Nature 372, 336-343 (1994); West, A. P. Jr. & Bjorkman, P. J. Crystal structure and immunoglobulin G binding properties of the human major histocompatibility complex-related Fc receptor. Biochemistry 39, 9698-9708 (2000)). Instead, the MHC class I fold of FcRn has evolved to bind to IgG and albumin.
FcRn, predominantly localized in acidic endosomal compartments, encounters proteins continuously taken up by fluid-phase endocytosis. The low pH in the vesicles allows ligand binding. FcRn-ligand complexes are then exported to the cell surface, where exposure to the higher physiological pH of the bloodstream triggers release of the ligands by a so-called kiss-and-run exocytotic mechanism (Ward et al. Adv. Immunol. 103: 77-115, 2009; Ober et al., Proc. Natl. Acad. Sci. USA 101:11076-11081, 2004). Proteins that do not bind to FcRn progress to lysosomes for proteolytic degradation.
FcRn plays a role in half-life regulation as demonstrated, e.g., using genetically modified mice, as mice lacking FcRn genetic deficiency of FcRn are both hypoalbuminemic and hypogammaglobulinemic (D C, Robinson J M, et al. Albumin turnover: FcRn-mediate recycling saves as much albumin from degradation as the liver produces. Am J Physiol Gastrointest Liver Physiol. 2005; 290(2): G352-60); Roopenian D C, Christianson G J, Sproule T J, et al. The MHC class I-like IgG receptor controls perinatal IgG transport, IgG homeostasis, and fate of IgG-Fc-coupled drugs. J Immunol. 2003; 170(7):3528-33). A human example is familial hypercatabolic hypoproteinemia, where deficiency in FcRn expression results in abnormally low levels of both ligands. Furthermore, variants of HSA with carboxy-terminal truncations have unusual low serum levels. In line with this, the so-called HSA-Bartin variant, known to lack the C-terminal DIII except for the first 29 amino acids, shows severely reduced FcRn binding.
In some conditions such as acute/subacute toxigenic exposures or chronic conditions where albumin becomes pathogenic due to disease-related modifications, reduction in binding of albumin to FcRn would be beneficial.
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