Magic™ Humanized PD-1/TIGIT Dual Immune Checkpoint Knock-In Mice

The immune response plays a vital role in staving off cancer; however, mechanisms of immunosuppression hamper productive anti-tumor immunity. Creative Biolabs, who always focuses on the research highlight of antibody-based drug discovery, has successfully established an efficient Magic™ “humanized” animal platform to offer humanized PD-1/TIGIT dual immune checkpoint knock-in mice for our clients all over the world.

PD-1 and TIGIT Immune Checkpoint Molecules

Programmed death-1 (PD-1, also known as CD279), is an immune checkpoint protein present on the surface of activated T cells. Several studies have shown that PD-1, interacting with its ligand PD-L1, regulates the induction and maintenance of peripheral tolerance and protect tissues from autoimmune attack. What's more, PD-1 and PD-L1 are also involved in attenuating infectious immunity and tumor immunity and facilitating chronic infection and tumor progression. More recently, PD-1 antibodies have been proved to be highly effective in various cancers including melanoma, non-small-cell lung cancers, Merkel-cell carcinoma, and renal cancer. TIGIT (T cell immunoglobulin and ITIM domain), which is regarded as a novel member of the CD28 family, is a receptor of the Ig superfamily that is specifically expressed in immune cells where it functions as a co-inhibitory receptor. TIGIT is expressed on activated T cells and is also found on NK cells, memory T cells, a subset of Treg cells as well as follicular T helper (Tfh) cells, and binds the adhesion molecules CD155 (Necl-5, also known as PVR) and CD112 (nectin-2, also known as PRR2 or PVRL2) with high and low affinity, respectively.

Combination of Anti-PD-1 and Anti-TIGIT Immunotherapies

It has been reported that TIGIT exerts its immunosuppressive effects by enhancing IL-10 production by DCs through CD155, impeding CD4⁺ T cell proliferation and function, and TIGIT also exerts CD4⁺ T cell–intrinsic inhibitory effects via recruitment of SHP phosphatases that suppress cytokine production and proliferation and competes with CD226 for PVR binding.

Since targeting the PD-1-PD-L1 pathway alone does not result in complete restoration of T cell function, and in some cancers targeting the PD-1-PD-L1 pathway does not restore T cell function at all, there is a need to identify other molecules and inhibitory pathways that are involved in T cell exhaustion. TIGIT blockade has demonstrated combination activity when combined with checkpoint inhibitors anti-PD1 and anti-PD-L1 in preclinical models. Some colon cancer models showed that the combination inhibited tumor growth and resulted in complete rejection of the tumors, significantly increasing mice survival as compared to control group or to anti-TIGIT, anti-PD1 or anti-PDL1 alone.

Magic™ Humanized PD-1/TIGIT Dual Immune Checkpoint Knock-In Mice Fig.1. Putative Molecular Mechanisms Involved in Synergy Observed during coblockade. (Pauken and Wherry, 2014)

Development of Humanized PD-1/TIGIT Dual Immune Checkpoint Knock-In Mice

In recent years, immune checkpoint blockade therapies have been shown of substantial clinical benefit in cancer patients. However, current immune checkpoint-based therapies are effective only in a subset of patients and acquired resistances lead to additional challenges. Discovering new immune checkpoint targets and combining checkpoint inhibitors might help to overcome the limitations. Confirming whether antibodies designed to block distinct immune checkpoint pathways can act synergistically has drawn great attention in research and development of combination immunotherapy drugs. As a world leader in this field, Creative Biolabs has already launched an array of well-characterized Magic™ “humanized” dual immune checkpoint mouse models, and both humanized transgenes are validated to be correct and functional. Now, we are proud to provide the humanized PD-1/TIGIT dual immune checkpoint knock-in mice for our clients worldwide. Please feel free to contact us for more detailed information.