Activation of human glucocorticoid-induced tumor necrosis factor receptor (hGITR) could inhibit the regulatory T cells (Tregs) suppressing the immune response and promote the effector T cells killing tumor cells as well. hGITR agonist antibody combining with the anti-hPD-1 antibody could enhance the efficacy in cancer patients, especially in those who cannot benefit from the anti-hPD-1 antibody alone. Creative Biolabs has successfully established an optimized Magic™ “humanized” animal platform to offer specialty manipulated the hPD-1/hGITR dual humanized mice for our clients all over the world.

hPD-1/hGITR Molecule

Human programmed cell death protein 1 (hPD-1) is a receptor protein on the surface of T cells. The ligation of hPD-1 and its ligand hPD-L1, could emit a downregulatory signal to the host immune system to protect autologous cells from immune attack, maintaining immune tolerance. However, this mechanism exists in tumor cells and assists tumor cells to escape the cytotoxic T cells attack.

hGITR belongs to the tumor necrosis factor receptor superfamily (TNFRSF) and it is the 18th member of this superfamily. It is a costimulatory molecule expressing on the membrane surface of both effector T cells (Teffs) and Tregs. The expression level of hGITR varies due to physiological status, and it could be increased by tumor antigens. In preclinical studies, GITR has been found with the capacity of causing T cell proliferation and enhancing the immunity by activating Teffs. Besides, activating the hGITR pathway can block the inhibitory effect of Tregs.

hPD-1/hGITR Signal Pathways

hPD-1 binding to hPD-L1 between T cells and tumor cells is one of the mechanisms under immune evasion. Blockade the hPD-1/hPD-L1 pathway by anti-hPD-1 antibody could effectively activate the anti-tumor activity. The anti-hPD-1 antibody has been confirmed its efficacy in multiple cancers and now, it has been widely used in clinical therapy. The function of the hGITR pathway in Tregs and Teffs is different. The hGITR pathway could suppress the inhibitory activity of Tregs and prolong the survival of Teffs. The Teffs are the main force to kill tumor cells on the front line. Activating hGITR on the surface of Teffs can promote their proliferation and survival, thus enhancing the anti-tumor immunity. Importantly, if the population and activity of Teffs can be improved by activating the hGITR pathway, it is possible to improve the effects of existing immunotherapy (such as anti-hPD-1 antibody therapy). At the same time, when the antibody binds to hGITR on the surface of Tregs, the hGITR pathway can accelerate Tregs failure. Tregs, which inhibit the function of Teffs, induces its failure to indirectly play a role in activating Teffs function.

Mechanism of GITR-mediated antitumor activity. Fig.1 Mechanism of GITR-mediated antitumor activity. (Knee, 2016)

Development of hPD-1/hGITR Dual Humanized Mice

Currently, hGITR is a costimulatory checkpoint molecule that immunologists are keen to study. Activating the hGITR pathway could increase the number and augment the function of Teffs, which would improve the anti-tumor activity of the anti-hPD-1 antibody. Thus, the combinational utilization of the anti-hGITR agonist antibody and anti-hPD-1 antibody might exert promising efficacy in cancer treatment. With advanced technology, Creative Biolabs provides multiple well-established Magic™ “humanized” animal models, including the hPD-1/hGITR dual humanized mice. If you are interested in these humanized models and not sure which suits your study project, please feel free to contact us for further discussion. Our scientists will provide you with professional preclinical CRO services.

Creative Biolabs also offers other various Humanized Mouse Models you may be interested in:

Reference

  1. Knee, D. A.; et al. Rationale for anti-GITR cancer immunotherapy. Eur J Cancer. 2016, 67: 1-10.

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