• Gene Information: CD98HC, encoded by the SLC3A2 gene, is a critical type II transmembrane glycoprotein. It functions primarily as a heavy chain that covalently associates via a disulfide bond with various light chains, such as LAT1 or LAT2. 
• Protein Expression: In normal physiological conditions, CD98HC is expressed moderately across various tissues, including the kidneys, intestinal epithelium, and placenta, where it maintains regular metabolic and transport functions. However, its expression is markedly upregulated in proliferating cells, activated lymphocytes, and a wide array of human malignancies, including carcinomas and melanomas. 
• Signaling Pathway: CD98HC actively participates in intricate intracellular signaling networks by interacting directly with beta-1 and beta-3 integrins. This interaction modulates integrin-mediated signal transduction, promoting cell adhesion, migration, spreading, and survival. 
• Application: Given its prominent role in cancer cell metabolism and immune activation, CD98HC has emerged as a promising therapeutic target in oncology and immunology. CD98hc-targeting antibodies or ligands enable receptor-mediated transcytosis across the blood-brain barrier, serving as an efficient shuttle to transport therapeutic drugs, proteins, and nanoparticles directly into the central nervous system.

FcRn MOA: pH-Dependent Binding of IgG to FcRn

• IgG Binding to FcRn at Acidic pH 

In acidic environments such as endosomes, IgG binds strongly to FcRn, facilitating its transport and recycling.

• IgG Dissociation at Neutral pH

 Upon reaching the plasma membrane, the pH shifts to near-neutral, triggering the release of IgG from FcRn into the extracellular fluid.

CD98HC

•  The exons 2-10 of mouse CD98HC gene that encode extracellular domain are replaced by human CD98HC exons 4-12. 
• The genomic region of mouse CD98HC gene that encodes cytoplasmic portion is retained. The promoter, 5’UTR and 3’UTR region of the mouse gene are also retained. 
• The chimeric CD98HC expression is driven by endogenous mouse CD98HC promoter, while mouse CD98HC gene transcription and translation will be disrupted.

 FcRn

•  The human full-length FCGRT cDNA was inserted into the Fcgrt exon 2 of wild-type mice. 
• The FcRn protein expression will be driven by endogenous mouse FcRn promoter, while mouse FcRn gene transcription and translation will be disrupted.

B-hCD98HC/hFcRn mice are generated by mating B-hCD98HC mice (110983) with B-hFcRn mice (110001).

Protein expression analysis of CD98HC in homozygous B-hCD98HC/hFcRn mice. Various tissue lysates were collected from wild-type C57BL/6JNifdc mice (+/+) and homozygous B-hCD98HC/hFcRn mice (H/H), and then analyzed by western blot with anti-CD98HC antibody (Proteintech, 15193-1-AP). 40 μg total protein was loaded for western blotting analysis. Human CD98HC was exclusively detected in heart, liver, spleen, lung, kidney, brain, stomach, colon, uterus and eyeballs from homozygous B-hCD98HC/hFcRn mice.

Protein expression analysis of FcRn in homozygous B-hCD98HC/hFcRn mice. Various tissue lysates were collected from wild-type C57BL/6JNifdc mice (+/+) and homozygous B-hCD98HC/hFcRn mice (H/H), and then analyzed by western blot with anti-FcRn antibody (human FcRn: NOVUS, NBP1-89128; mouse FcRn: R&D, AF6775). 40 μg total protein was loaded for western blotting analysis. mFcRn was only detected in heart, liver, spleen, lung, kidney, skeletal muscle, stomach, colon and uterus from wild-type C57BL/6JNifdc mice. hFcRn was exclusively detected in heart, liver, spleen, lung, kidney, skeletal muscle, stomach, colon and uterus from homozygous B-hCD98HC/hFcRn mice.

Serum pharmacokinetic (PK) analysis of anti-CD98HC antibody in wild-type and humanized TFR1/FcRn mouse strains. (A) Scheme design. Male mice (n = 9 per group) from wild-type C57BL/6 mice (G1), B-hFcRn mice (G2), B-hCD98HC mice (G3) and B-hCD98HC/hFcRn mice (G4) received a single intravenous (i.v.) dose of 10 mg/kg anti-human CD98HC antibody (monovalent). Blood samples were collected at 0.25 h, 6 h, 24 h, and on days 3, 5, 7, 10 and 14 post-administration. (B) Serum concentrations of anti-CD98HC antibody were measured by ELISA. Mice lacking human CD98hc (G1, G2) displayed typical slow IgG clearance. Accelerated antibody elimination was observed in humanized CD98HC mice (G3 and G4) due to target-mediated drug disposition (TMDD). Binding of the mAb to cell-surface human CD98hc triggers receptor internalization and lysosomal degradation of antibody-antigen complexes. G4 showed the most rapid clearance due to combined human CD98hc-dependent TMDD and human FcRn background.

Brain pharmacokinetic (PK) analysis of anti-CD98HC antibody in wild-type and humanized TFR1/FcRn mouse strains. (A) Scheme design. Male mice (n = 9 per group) from wild-type C57BL/6 mice (G1), B-hFcRn mice (G2), B-hCD98HC mice (G3) and B-hCD98HC/hFcRn mice (G4) received a single intravenous (i.v.) dose of 10 mg/kg anti-human CD98HC antibody (monovalent). Brain tissues were collected on day 5 post-administration. (B) Brain parenchyma and whole brain concentrations of anti-CD98HC antibody were measured by ELISA. The test antibody specifically recognizes human CD98HC and does not cross-react with endogenous murine CD98HC, therefore brain penetration is not detectable in wild-type mice (G1, G2). Data are shown as mean ± SEM.