huALB/huFcRn Mouse

Neonatal Fc receptor (FcRn) is a cell surface receptor protein that binds to the Fc region of IgG antibodies. It is structurally similar to MHC class I molecules and is composed of an α-chain and β2-microglobulin (β2M). The α-chain of the FcRn receptor is encoded by the Fcγ receptor and transporter (FCGRT) gene, while β2-microglobulin is encoded by the β-2-microglobulin (B2M) gene. FcRn is expressed widely on epithelial cells, endothelial cells, and hematopoietic cells, and is found in various tissues and organs, including the intestine, placenta, kidney, and liver ^[1-2].

IgG antibodies are the most abundant immunoglobulins in human serum (about 75%), and play an important role in the immune response by defending against pathogens and toxins. Compared to other immunoglobulins, IgG has a high circulating level, a longer half-life, and the ability to be transferred from mother to offspring. These properties are closely related to its interaction with FcRn. FcRn binds to the Fc region of IgG, preventing IgG molecules from being degraded by lysosomes. This prolongs the in vivo half-life of IgG and is involved in the transport, maintenance, and distribution metabolism of IgG. In addition, the specific transport process of IgG from the mother to the fetus to provide the fetus with short-term passive immunity is also mediated by FcRn ^[1-2]. In addition to its protective role, IgG autoantibodies are also associated with many pathological conditions. Therefore, novel FcRn blocking therapies are an effective strategy to reduce the circulating levels of pathogenic IgG autoantibodies and to reduce IgG-mediated diseases. In addition, many drugs also utilize FcRn's protective mechanism for IgG by fusing or conjugating with the Fc portion of IgG to prolong its serum half-life and improve its pharmacokinetics. The FCGRT gene encodes the α-chain of the FcRn protein, and its homologous genes are present in most mammals.

The ALB gene encodes albumin, mainly produced in the liver, and is the most abundant protein in human plasma, accounting for 60% to 65% of total plasma protein. The proprotein encoded by ALB is processed to produce a functional protein, and the EPI-X4 peptide derived from this protein is an endogenous inhibitor of the CXCR4 chemokine receptor. Albumin plays a role in regulating plasma colloid osmotic pressure, helping to maintain blood circulation and isolating and transporting many metabolites within the body, especially insoluble hydrophobic metabolites ^[3]. Human Serum Albumin (HSA) is an important carrier protein involved in the transport of a variety of endogenous molecules, including hormones, fatty acids, and metabolic products, as well as exogenous drugs. As a natural carrier protein, HSA has multiple ligand binding sites and a plasma half-life of up to 19 days, making it a promising drug carrier. Several HSA-based drug delivery systems have been approved for clinical trials ^[4-5]. Albumin is also the primary transporter of zinc, calcium, and magnesium in plasma, binding approximately 80% of all plasma zinc and about 45% of circulating calcium and magnesium, with an affinity ranking order of zinc > calcium > magnesium. Additionally, albumin exhibits broad substrate-specific esterase-like activity, with enzymatic properties. It can also bind to the bacterial siderophore enterobactin, inhibiting enterobactin-mediated uptake of iron from transferrin by Escherichia coli, thus limiting iron availability and intestinal bacterial growth ^[6]. Diseases related to the ALB gene include hyperthyroxinemia, familial dysalbuminemic hyperthyroxinemia, and analbuminemia ^[7].

The huALB/huFcRn mice were obtained by crossbreeding huFcRn humanized mice (Catalog Number: C001701) with huALB humanized mice (Catalog Number: C001492). In this model, the gene sequence encoding the extracellular domain of the FCRN protein in the mouse Fcgrt gene was replaced with the corresponding gene sequence from the human FCGRT gene, which is the binding site for the FCRN and IgG antibody Fc structure. Additionally, the mouse Alb gene sequence (including UTR regions) was replaced in situ with the human ALB gene sequence. Therefore, the huALB/huFcRn mice can be used for in vivo studies of human IgG antibodies, drug development using human serum albumin (HSA) as a carrier, as well as for pharmacodynamic and pharmacokinetic studies.