Hepatitis A virus cellular receptor 2 (HAVCR2) (TIM-3)

Hepatitis A virus cellular receptor 2 (HAVCR2), widely known as TIM-3, is a critical immune checkpoint receptor expressed on various immune cells, including CD4+ Th1 cells, CD8+ cytotoxic T cells, NK cells, and myeloid cells (UniProt P37244). The extracellular portion of TIM-3 features a characteristic immunoglobulin variable (IgV) domain containing a unique pocket formed by the FG and CC′ loops, known as the orthosteric cleft or metal ion-dependent ligand binding site (MILIBS) (PubMed: 26063006). This cleft is essential for the recognition of ligands such as phosphatidylserine (PtdSer) on apoptotic cells and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which are vital for its immunosuppressive functions (PubMed: 25801879). In the tumor microenvironment, chronic ligand binding at this site leads to T-cell exhaustion and limits the efficacy of anti-tumor immune responses, often correlating with resistance to PD-1/PD-L1 therapies (PubMed: 28235144). Therapeutic antibodies currently in clinical development, such as Sabatolimab, are designed to target this IgV domain to disrupt ligand interactions and restore the functional capacity of exhausted T cells in patients with advanced malignancies and myeloid disorders (ClinicalTrials.gov: NCT02608268).

Other names

T-cell immunoglobulin and mucin-domain containing-3TIMD3CD366T-cell membrane protein 3

Antagonism of the TIM-3 receptor by binding to the IgV domain (specifically the FG-CC′ cleft) to block interactions with ligands such as phosphatidylserine and galectin-9, thereby reversing T-cell exhaustion and enhancing anti-tumor immunity.