Recombinant Human LAG-3 Fc Chimera Protein, CF

LAG-3 (Lymphocyte activation gene-3), designated CD223, is a 70 kDa type I transmembrane protein that is a member of the immunoglobulin superfamily (IgSF) (1, 2). LAG-3 shares approximately 20% amino acid sequence homology with CD4, but has similar structure and binds to MHC class II with higher affinity, providing negative regulation of T cell receptor signaling (1, 2). Human LAG-3 cDNA encodes 525 amino acids (aa) that include a 28 aa signal sequence, a 422 aa extracellular domain (ECD) with four Ig-like domains, a  transmembrane region and a highly charged cytoplasmic region. Within the ECD, human LAG-3 shares 70%, 67%, 76%, and 73% aa sequence identity with mouse, rat, porcine, and bovine LAG-3, respectively. LAG-3 is expressed on activated CD4⁺ and CD8⁺ T cells, NK cells, and plasmacytoid dendritic cells (pDC), but not on resting T cells (1-3). LAG-3 on activated CD4⁺CD25⁺ T_reg cells plays a role in their suppressive activity (4). LAG-3 limits the expansion of activated T cells and pDC in response to selected stimuli (3-5). A soluble 54 kDa form, sLAG-3, can be shed by metalloproteinases ADAM10 and TACE/ADAM17 (6, 7). While monomeric sLAG-3 itself may be inactive, shedding allows for normal T cell activation by removing negative regulation (7). Binding of a homodimerized sLAG-3/Ig fusion protein to MHC class II molecules induces maturation of immature DC, and secretion of cytokines such as IFN-gamma and TNF-alpha by type 1 cytotoxic CD8⁺ T cells and NK cells (8, 9). sLAG-3/Ig has been used as a potential adjuvant to stimulate a cytotoxic anti-cancer immune response (9, 10). In mice, deletion of LAG-3 and another negative regulator, PD-1, facilitates anti-cancer response but also blocks self-tolerance and increases susceptibility to autoimmune diseases (11, 12). In humans, antibody-mediated down‑regulation of LAG-3 and PD-1 allows more effective control of chronic malaria, while in NOD (non‑obese diabetic) mice, deletion of LAG-3 alone accelerates diabetes (12-14).