More and more evidence suggests that elevated expression of inhibitory receptors on tumor antigen-specific T cells is one of the mechanisms by which tumors evade host immune surveillance. Blockade of certain individual inhibitory receptor with specific antibodies has shown significant efficacy in overcoming immune suppression and mediating tumor regression. Recently, several studies indicate that multiple inhibitory receptors (such as CD160, KLRG-1, TIM-3, BTLA, and LAG-3) are often co-expressed on tumor-antigen specific CD8+ T cells. Moreover, it has been reported that dual simultaneous blockade of inhibitory receptors synergistically reverse the exhausted state of T cells and render them more functional than single blockade of the receptors. With years of experience in antibody-based drug discovery and animal model, Creative Biolabs has successfully established the validated Magic™ “humanized” animal platform, which can provide our clients with humanized PD-1/ LAG-3 dual immune checkpoint knock-in mice worldwide.
Combination of PD-1 and LAG-3 Signaling for Immunotherapies
Programmed death-1 (PD-1) is a type I transmembrane protein that expressed on activated T cells as well as other immune cells including natural killer (NK) cells, B cells, and some myeloid cells. As an inhibitory receptor, PD-1 has two known ligands, programmed cell death protein 1 ligand 1 (PD-L1; also known as B7H1 and CD274) and PD-L2 (also known as B7DC and CD273), which are often overexpressed on tumor cells. The interactions of PD-1 and its ligands deliver a negative signal to T cells to suppress the immune response. T cells express PD-1 only following activation when it functions to limit the effector phase of T cell differentiation. PD-1 plays a crucial role in tolerance to self-antigens and can also function as a ‘rheostat' that modulates T cell responses. Chronic infection models have shown that blocking PD1 interactions can reverse T cell exhaustion. Tumors can evade immune response by signaling through PD1; therefore, blocking PD1 signaling pathway can induce an anti-tumor response.
LAG-3 is not expressed by resting T cells but is upregulated several days after T cell activation. The unique features and functions of LAG-3 make it a promising target for immune modulation, including its well-established role in the negative regulation of T cell function. Blocking LAG-3 signaling results in augmenting T cell proliferation and cytokine production. It has been previously demonstrated that a subset of tumor antigen-specific CD8+ T cells co-expressing LAG-3 and PD-1 are impaired in TNF-α and IFN-γ production and that simultaneous blockade of LAG-3 and PD-1 restores effector function of human ovarian tumor antigen-specific T cells to a level that is above the additive effects of single blockade of LAG-3 or PD-1 alone.
Fig.1. Receptors that negatively regulate T cell function. (Nguyen & Ohashi, 2015)
Development of Humanized PD-1/LAG-3 Dual Immune Checkpoint Knock-In Mice
There is no doubt that LAG-3 and programmed cell death 1 (PD-1) have been studied most extensively in preclinical models and in clinical trials. Moreover, the latest clinical data combining different blockade in cancer patients shows that dual blockade of the PD-1 pathway and LAG-3 has been shown in mice and humans to be more effective for anti-tumor immunity than blocking either molecule alone. As a world leader in the industry of animal model, Creative Biolabs has already established a series of well-established Magic™ “humanized” animal models, including the humanized PD-1/LAG-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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