TIM-3 Immune Checkpoint Molecule for Drug Development
Overview of TIM-3
T-cell immunoglobulin and mucin domain 3 (TIM-3) is an immunoglobulin (Ig) and mucin domain-containing cell surface molecule. As a negative regulatory immune checkpoint, TIM-3 is detected in different types of immune cells, including B cells, macrophages, T cells, regulatory T cells (Tregs), nature killer (NK) cells, dendritic cells (DCs), and mast cells.
Structure and Signaling
A unique feature of TIM-3 is its lack of known inhibitory signaling motifs in its cytoplasmic tail. Different from other checkpoint receptors like PD-1 and TIGIT, TIM-3 lacks classical inhibitory immunoreceptor tyrosine-based inhibition or immunoreceptor tyrosine-based switch signaling motifs in its cytoplasmic tail. HLA-B-associated transcript 3 (Bat 3) and SH2 domain-containing protein Fyn interact with the conserved tyrosine Y256 and Y263 in its cytoplasmic tail. Upon T-cell activation, TIM-3 is recruited to the immunological synapse where Bat3 binds to the cytoplasmic tail of TIM-3 and recruits the active, catalytic form of lymphocyte-specific protein tyrosine kinase (Lck). However, when TIM-3 is engaged by ligand, the conserved tyrosine residues in the cytoplasmic tail become phosphorylated, leading to the release of Bat3, thereby allowing TIM-3 to exert its inhibitory function.
So far, four ligands for TIM-3 have been identified: galectin-9, phosphatidylserine (PtdSer), high-mobility group protein B1 (HMGB1), and CEACAM-1.
Galectin-9 binding results in oligomerization of TIM-3 on the cell surface, leading to the release of Bat3 from the intracellular tail of TIM-3. TIM-3-galectin-9 interaction contributed to immune dysfunction and poor prognosis.
TIM-3-PtdSer interaction is essential for mediating phagocytosis of apoptotic cells by TIM-3-expressing CD8+ DCs and subsequent cross-presentation of the apoptotic cell-associated antigens to CD8+ T cells.
TIM-3 on DCs serves as a molecular trap for HMGB1 and inhibits the recruitment of nucleic acids into endosomes, subsequently preventing the activation of DCs in the tumor microenvironment.
CEACAM1 can bind TIM-3 both extracellularly and intracellularly. The extracellular binding can trigger the release of Bat3 from TIM-3, thus allowing TIM-3-mediated inhibition of TCR signaling. The intracellular binding is important for the maturation of TIM-3 protein.
Fig.1 Model of Tim-3 signaling in T cells. (Acharya, 2020)
Clinical Development of TIM-3 Antibodies
Extensive data in preclinical and clinical trials have shown the advantage of blocking TIM-3, particularly in conjunction with PD-1 blockade, in improving antitumor immunity and the development of TIM-3 as an immunotherapeutic target.
Services at Creative Biolabs
Therapeutics that block inhibitory receptors or activate immune-stimulatory checkpoint receptors are powerful agents for restoring anti-tumor immune responses. Creative Biolabs has rich experience in immune-oncology research and offers an expanding menu of immune checkpoint services to enable comprehensive drug development.