Immune checkpoint inhibitors have been regarded as a powerful new class of anticancer therapy. They have changed the clinical treatment method for a series of tumor types, including melanoma, non-small cell lung cancer, breast cancer, etc. Nowadays, scientists are focused on discovering new drugs that target various immune checkpoint, with an emphasis on understanding non-response. Some studies indicate that multiple inhibitory receptors are upregulated on hypofunctional tumor-infiltrating lymphocytes (TILs), thus blocking multiple inhibitory receptors seems to be necessary for increasing the response rate. With extensive experience and advanced technology, Creative Biolabs currently provides our clients with the Magic™ “humanized” mouse models, including the humanized PD-L1/TIM-3 dual immune checkpoint knock-in mice.
PD-L1 and TIM-3 Immune Checkpoint Pathway
The programmed cell death-ligand 1 (PD-L1), also known as B7-H1 or CD274, is commonly expressed on the surface of dendritic cells or macrophages. PD-L1 belongs to the family of immune checkpoint proteins and act as a co-inhibitory factor, which can suppress or limit the development of the T cell response. When bound to PD-1 receptors on the activated T cells, PD-L1 expressed on the tumor cells leads to the inhibition of the cytotoxic T cells.
T cell immunoglobulin and mucin domain 3 (TIM-3) has been recognized as a member of the TIM gene family and acts as a T cell inhibitory receptor. It is expressed on Th1, Th17, CD8+ T cells. There are four relevant ligands of TIM-3: galectin-9 (Gal-9), high mobility group protein B1 (HMGB1), phosphatidylserine (PtdSer), and carcinoembryonic antigen cell adhesion molecule 1 (Ceacam-1). Binding of TIM-3 and its ligands has been found to be involved in suppressing Th1 and Th17 responses and inducing peripheral immune tolerance, indicating an inhibitory role of TIM-3 in T cell-mediated immune responses.
Fig.1. Overview of the immune checkpoint molecules PD-1 and TIM-3. (Tieu, et al., 2014)
Combination of Anti-PD-L1 and Anti-TIM-3 Immunotherapies
The selective expression on intratumoral T cells may permit more precise treatment by the targeting of tumor-infiltrating T cells, potentially reducing non-specific toxicity. Additionally, signaling downstream of TIM-3 is rather distinct from that of PD-L1. Compared to PD-1/PD-L1 pathway, TIM-3 can both enhance and inhibit proximal signaling in T cells, depending on the cellular context. Accordingly, the distinctive expression and intracellular signaling show a significant potential for targeting TIM-3 in combination with previous PD-L1-based immunotherapy of cancer. Several studies have demonstrated that combining a single dose of tumor-reactive T cells with blockade of both PD-L1 and TIM-3 led to greater control of tumor growth than combining it with blockade of either alone.
Development of Humanized PD-L1/TIM-3 Dual Immune Checkpoint Knock-In Mice
A thorough understanding of the roles of TIM-3 that expressed on different cell types via various animal tumor models is critical for further drug development targeting TIM-3 and design of combination therapy with PD-L1 mAbs. Currently, Creative Biolabs has already established an array of validated Magic™ “humanized” mouse models, including the humanized PD-L1/TIM-3 dual immune checkpoint knock-in mice with the assurance for effectiveness of both humanized transgenes. Our experienced scientists are ready to serve you with the most professional technical support. Please feel free to contact us for more detailed information.
Creative Biolabs also offers other various Humanized Mouse Models you may be interested in:
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