| Background | Lymphocyte activation gene 3 protein (Ieramilimab) is a ~57 kDa protein. Inhibitory receptor on antigen activated T-cells (1,2,3,4). Delivers inhibitory signals upon binding to ligands, such as MHC class II, its main ligand present at the surface of antigen-presenting cells (APCs), and FGL1, which is secreted by hepatocytes and certain types of tumor cells (5,6,2,7,8,4,9). Ligand-binding initiates a signaling that inhibits the T-cell receptor (TCR) in the immunological synapse, preventing T-cell activation (10). Mechanistically, ligand-binding promotes (1) ubiquitination of the KIEELE motif, unleashing the RRFSALE motif from the membrane and (2) leading to the formation of condensates with the TCR component CD3E, thereby disrupting the association between CD3E and LCK and preventing TCR activation (10,11). May inhibit antigen-specific T-cell activation in synergy with PDCD1/PD-1.
References:
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4. Huard, B. et al. (1996) European journal of immunology 26, 1180-6. PMID: 8647185
5. Wang, J. et al. (2019) Cell 176, 334-347.e12. PMID: 30580966
6. MacLachlan, BJ. et al. (2021) European journal of immunology 51, 331-341. PMID: 32920841
7. Petersen, J. et al. (2024) Science immunology 9, eads5122. PMID: 39671469
8. Huard, B. et al. (1995) European journal of immunology 25, 2718-21. PMID: 7589152
9. Jiang, Y. et al. (2025) Cell 188, 2354-2371.e18. PMID: 40101708 |
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