Combined Therapy of PD-1 and TIM-3

Introduction to PD-1 and TIM-3

The programmed death 1 (PD-1) is a transmembrane receptor found on T cells from the immunoglobulin B7-CD28 family. PD-1 and its ligand PD-L1 are the most widely studied anticancer targets and the important immune checkpoint molecule.

T cell immunoglobulin and mucin-3 (TIM-3) is another immune checkpoint molecule expressed on activated human T cells, NK cells, and monocytes. Interaction of TIM-3 with its ligand, galectin-9, triggers cell death in Tim-3+ T cells. Thus, both TIM-3 and PD-1 can function as negative regulators of T cell responses.

Double Immune Checkpoint Blockade of PD-1 and TIM-3

Despite the exciting antitumor activity of antibodies targeting the PD-1 and PD-L1 immune checkpoint in some cancers, resistance to these therapies has increasingly been observed. In tumors progressing following response to anti-PD-1 treatment, upregulation of alternative immune checkpoints, notably TIM-3, is observed, which shows TIM-3 may be a biomarker associated with resistance to PD-1 blockade. Therefore, targeting immune-related co-inhibitors has the potentials to expand the effectiveness of PD-1/PD-L1 blockade.

• Preclinical stage

Preclinical studies indicate that TIM-3 is co-expressed with PD-1 on a large fraction of tumor-infiltrating lymphocytes (TILs) in mice bearing solid tumors. Co-expression of both checkpoint molecules reflects an exhausted phenotype, functionally defines by a T cell's reduced ability to proliferate and secrete IFN-γ, IL-2, and tumor necrosis factor α (TNF-α). Therefore, the combined use of TIM-3 blockade with PD-1 blockade could be more effective in improving antitumor immune responses than blockade of either the TIM-3 or PD-1 alone.

• Clinical stage

Dual TIM-3 plus PD-1 blockade is currently being analyzed in phase I/II trials. A multicenter phase I study evaluating the anti-TIM-3 antibody combined with an anti-PD-1 antibody is recruiting patients with advanced solid tumors. Furthermore, a phase II study is studying how well anti-TIM-3 antibody and anti-PD-1 antibody work in combination in treating patients with locally advanced or metastatic liver cancer. Thus, combination therapy targeting PD-1 and TIM-3 may be a potential strategy to overcome T cell energy.

Fig.1 PD-1, TIM-3, and LAG-3 blockade. (Anderson, 2016)

Services at Creative Biolabs

Combining state-of-the-art technology with personal service and attention, Creative Biolabs offers a series of custom services for immune checkpoint PD-1 and TIM-3, including but not limited to:

• Immune Checkpoint Antibody Development
• Immune Checkpoint Targeted Small Molecule Drug Development
• Immune Checkpoint Assays
• Custom Immune Checkpoint Protein Development
• Immune Checkpoint Targeted Peptide Development
• Preclinical Research for Immune Checkpoint Drugs

Please do not hesitate to contact us for more detailed information.

Reference

1. Anderson, A.C.; et al. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity. 2016, 44(5), pp.989-1004.

All listed customized services & products are for research use only, not intended for pharmaceutical, diagnostic, therapeutic, or any in vivo human use.