Co-inhibitory or immune checkpoint receptors have a key function in the maintenance of immune homeostasis: their expression on effector T cells allows the proper contraction of effector T cell responses and their expression on regulatory T (Treg) cells ensures the proper function of Treg cells to control effector T cells. Recently, the role of co-inhibitory receptors has come to the forefront in human cancer and chronic viral infection where these receptors are highly expressed and are being targeted clinically to improve anti-tumor and anti-viral T cell responses. As a world leader in the industry of anti-tumor drug discovery, Creative Biolabs has successfully launched a well-established Magic™ “humanized” animal platform to offer humanized PD-1/TIM-3 dual immune checkpoint knock-in mice for our worldwide clients.
Combination of Anti-PD-1 and Anti-TIM-3 Immunotherapies
Programmed cell death 1, which is also termed as PD-1 and CD279, is an immune checkpoint protein present on the surface of activated T cells. PD-1 has been identified as a marker of exhausted T cells in chronic disease states, and blockade of PD-1-PD-1L interactions has been shown to partially restore T cell function. There are several evidence that implicate the PD-1-PD-L1 pathway in T cell exhaustion in cancer. PD-1 is expressed on tumor-infiltrating CD8+ T cells in multiple solid tumors and on antigen-specific CD8+ T cells in hosts with nonsolid tumors, and these PD-1+ T cells are dysfunctional. PD-L1 is also expressed at high levels in several different tumor cells, and high expression of PD-L1 on tumors is strongly associated with poor prognosis. It has been demonstrated that interference with PD-1-PD-L1 signaling, either through antibody blockade or PD-1 deficiency, can improve clinical outcome and restore functional T cell responses in several cancers. Interaction of Tim-3 with its ligand, galectin-9, triggers cell death in Tim-3+ T cells. T cell immunoglobulin mucin (TIM-3) is a molecule originally identified as being selectively expressed on IFN-γ-secreting Th1 and Tc1 cells. A study in patients with HIV has shown that TIM-3 is up-regulated on exhausted CD8+ T cells. As above, both Tim-3 and PD-1 can function as negative regulators of T cell responses.
Fig.1. Non-redundant suppressive effects of checkpoint receptors. (Li, et al., 2017)
Positive effect of targeting the TIM-3 and PD-1 signaling pathway in cancer, along with the previous demonstrations that blockade of either the PD-1 or TIM-3 signaling pathways can improve T cell function in the context of chronic infections, raised the possibility that combined targeting of these two pathways may prove to be the most efficacious means to restore anti-tumor immunity in vivo.
Development of Humanized PD-1/TIM-3 Dual Immune Checkpoint Knock-In Mice
It has been reported that combined treatment with anti-Tim-3 and anti-PD-L1 resulted in a dramatic reduction in tumor growth, even complete tumor regression. Dual therapy with anti-TIM-3 antibody and anti-PD-1 antibody is regarded as a promising novel immunotherapeutic strategy. Creative Biolabs, who always focuses on the highlights of oncology, has launched an array of well-characterized Magic™ “humanized” animal models, which can provide you with the humanized PD-1/TIM-3 dual immune checkpoint knock-in mice. Please feel free to contact us for more detailed information.
Creative Biolabs also offers other various Humanized Mouse Models you may be interested in:
Reference
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