TIGIT Target - Journey.

Recently, Roche published the early data of its monoclonal antibody tiragolumab monotherapy for some solid tumor patients, showing no response;On May 13, Roche announced the positive results of phase 2 cityscape test of tiragolumab combined with tecentriq (atezolizumab) for metastatic NSCLC,The results showed that the combined regimen was superior to tecentriq in terms of Orr and PFS.And a week ago, Seattle genetics announced that the first patient had been treated with sea-tigit, its tigit antibody.A series of news has focused our attention on tigit again.in this paper, the discovery of tigit target, the follow-up research and the research and development of antibody drugs targeting tigit are briefly introduced.the discovery and research of tigit (T-cell immunoreceptor with Ig and ITIM domains) was first discovered by the scientific research team of Genentech company, and the related work was published in Nature Immunology in January 2009.according to the article, the company's scientists found the target by combining two genome-wide search strategies: on the one hand, they selected genes with high specific expression on immune cells; on the other hand, they searched for genes with the structure of "extracellular immunoglobulin domain + type I transmembrane region + intracellular ITIM or tyrosine based activation motif".the combination of the two retrieval strategies resulted in multiple genes including tigit.previous retrieval data and RT-PCR results showed that tigit was specifically expressed on NK cells and T cells.also in this paper, they used fortebio octet system to screen the human secretory protein library (constructed by Genentech itself, known as the secret protein discovery initiative), and found that tigit could interact with PVR (CD155), pvrl2 and pvrl3 (higher affinity for PVR and pvrl3, and lower affinity for pvrl2).in addition, with the help of this interaction detection system, they found that tigit competitively binds to PVR with cd96 and CD226 (the other two proteins that can bind to PVR), suggesting that there is overlap between tigit and PVR.by flow cytometry, they found that the expression of tigit was the highest on CD4 + cd25hi Treg cells (the expression level was affected by the activation level of cells), and the expression level of tigit on CD8 + cells was lower than that on NK cells, while no obvious expression of tigit was detected on B cells.functional experiments showed that tigit inhibited the activity of T cells through the interaction with PVR on the surface of dendritic cells.so far, a new immune checkpoint protein has been identified.in October of the same year, ofer, Hebrew University, Israel The work of mandelboim laboratory was published in PNAS, which demonstrated that tigit expressed on human NK cells could inhibit the cytotoxicity of NK cells through the interaction with PVR and pvrl2, and this regulatory effect was directly realized by regulating its downstream signal pathway through the intracellular ITIM motif of tigit, which was different from tigit on the surface of T cells.in this paper, they also demonstrated that the receptor proteins DNAM-1 (CD226) and cd96 on NK cells can also interact with PVR, and DNAM-1 can recognize pvrl2. However, preliminary experimental results show that the inhibition of NK cells caused by tigit-pvr interaction is dominant in biological function. because PVR and pvrl2 are widely expressed in epithelial derived normal cells, tigit is believed that tigit can protect these cells from NK cell killing and can be regarded as a supplement to the protective effect of type I MHC. however, some tumor cells overexpress PVR and pvrl2, which can block the combination of tigit with them and play the killing effect of NK cells, is also a treatment strategy that can be considered. the work published in "immunity" in April 2014 showed that tigit was highly expressed on activated inhibitory Treg cells, which specifically inhibited Th1 cells and Th17 cells, but not Th2 cells, so as to inhibit the pro-inflammatory response of the body, which showed that tigit was involved in the regulation of different groups of T cells; in addition, some people also proposed that tigit plays an immune regulation role The effect is mainly dependent on Treg cells rather than CD8 + T cells. however, in December 2014, Genentech team published an article in cancer cell, which mentioned that tigit is highly expressed on the surface of tumor infiltrating T cells. Blocking tigit and PD-1 at the same time with antibodies can specifically enhance the anti-tumor effect of CD8 + T cells, while blocking CD226 will counteract the activation effect of blocking tigit. this work preliminarily demonstrated the inhibitory effect of tigit on CD8 + T function, and the feasibility of combination of tigit antibody and PD-1 antibody. many follow-up studies have elaborated the relationship between tigit and T cell activity and cancer progression in various types of cancer, including melanoma, acute myeloid leukemia, gastric cancer, etc., which fully proves that the high expression of tigit is closely related to the functional damage of T cells, aging and poor clinical manifestations of patients. these works constantly consolidate and enrich the theoretical basis of tigit and CD8 + T cells, and provide a theoretical basis for drug development around tigit. the above research on tigit focuses on T cells (mainly CD8 + T cells and Treg cells) and NK cells, and studies the relationship between the functions of these kinds of cells in different microenvironments and tigit. until the article blockade of the checkpoint receptor tigit prevention NK cell emission and elicits potent anti tumor immunity was published, the discussion on the effect of NK cells on the anti-tumor function of T cells (i.e. the possible mutual modulation based on tigit between the two types of cells) formally entered people's vision, which can be said to be a relatively important theoretical breakthrough. so far, the biological mechanism of tigit has a clear outline. the correlation between tigit monoclonal antibody and clinical manifestations of patients has been fully demonstrated, and the potential therapeutic effect of tigit targeted antibody on cancer has been predicted in a variety of cancer animal models. therefore, the development of antibody drugs around this target has gradually become popular in the industry. according to the search in the small volume, there are 11 research and development projects of monoclonal antibody drugs targeting tigit, which have entered the stage of clinical verification: project code, enterprise R & D stage, indications tiragolomab rocheph3, vibostolimab msdph1 / 2 melanoma, ab154arcusph2 non-small cell lung cancer and other bms-986207bms, Onoph2 solid tumor asp8374 astella Ph1 solid tumor etigilimab celgene, oncomed Ph1 solid tumor ibi939 Xinda biological Ph1 solid tumor eos884448 iteos therapeutics Ph1