{"id":14620,"date":"2021-12-06T19:10:21","date_gmt":"2021-12-06T13:40:21","guid":{"rendered":"https:\/\/www.delveinsight.com\/blog\/?p=14620"},"modified":"2022-02-10T18:43:58","modified_gmt":"2022-02-10T13:13:58","slug":"tigit-inhibitor-landscape","status":"publish","type":"post","link":"https:\/\/www.delveinsight.com\/blog\/tigit-inhibitor-landscape","title":{"rendered":"T-cell Immunoglobulin and ITIM domain (TIGIT) Inhibitor: An Insight into the Pipeline Development Activities, Major Collaborations, and Advancements"},"content":{"rendered":"<div id=\"ez-toc-container\" class=\"ez-toc-v2_0_76 counter-hierarchy ez-toc-counter ez-toc-white ez-toc-container-direction\">\n<p class=\"ez-toc-title\" style=\"cursor:inherit\">Table of Contents<\/p>\n<label for=\"ez-toc-cssicon-toggle-item-69efbba4e812c\" class=\"ez-toc-cssicon-toggle-label\"><span class=\"\"><span class=\"eztoc-hide\" style=\"display:none;\">Toggle<\/span><span class=\"ez-toc-icon-toggle-span\"><svg style=\"fill: #999;color:#999\" xmlns=\"http:\/\/www.w3.org\/2000\/svg\" class=\"list-377408\" width=\"20px\" height=\"20px\" viewBox=\"0 0 24 24\" fill=\"none\"><path d=\"M6 6H4v2h2V6zm14 0H8v2h12V6zM4 11h2v2H4v-2zm16 0H8v2h12v-2zM4 16h2v2H4v-2zm16 0H8v2h12v-2z\" fill=\"currentColor\"><\/path><\/svg><svg style=\"fill: #999;color:#999\" class=\"arrow-unsorted-368013\" xmlns=\"http:\/\/www.w3.org\/2000\/svg\" width=\"10px\" height=\"10px\" viewBox=\"0 0 24 24\" version=\"1.2\" baseProfile=\"tiny\"><path d=\"M18.2 9.3l-6.2-6.3-6.2 6.3c-.2.2-.3.4-.3.7s.1.5.3.7c.2.2.4.3.7.3h11c.3 0 .5-.1.7-.3.2-.2.3-.5.3-.7s-.1-.5-.3-.7zM5.8 14.7l6.2 6.3 6.2-6.3c.2-.2.3-.5.3-.7s-.1-.5-.3-.7c-.2-.2-.4-.3-.7-.3h-11c-.3 0-.5.1-.7.3-.2.2-.3.5-.3.7s.1.5.3.7z\"\/><\/svg><\/span><\/span><\/label><input type=\"checkbox\"  id=\"ez-toc-cssicon-toggle-item-69efbba4e812c\"  aria-label=\"Toggle\" \/><nav><ul class='ez-toc-list ez-toc-list-level-1 ' ><li class='ez-toc-page-1 ez-toc-heading-level-2'><a class=\"ez-toc-link ez-toc-heading-1\" href=\"https:\/\/www.delveinsight.com\/blog\/tigit-inhibitor-landscape\/#TIGIT_Structure\" >TIGIT Structure<\/a><\/li><li class='ez-toc-page-1 ez-toc-heading-level-2'><a class=\"ez-toc-link ez-toc-heading-2\" href=\"https:\/\/www.delveinsight.com\/blog\/tigit-inhibitor-landscape\/#TIGIT_Expression\" >TIGIT Expression<\/a><\/li><li class='ez-toc-page-1 ez-toc-heading-level-2'><a class=\"ez-toc-link ez-toc-heading-3\" href=\"https:\/\/www.delveinsight.com\/blog\/tigit-inhibitor-landscape\/#TIGITs_Ligands\" >TIGIT\u2019s Ligands<\/a><\/li><li class='ez-toc-page-1 ez-toc-heading-level-2'><a class=\"ez-toc-link ez-toc-heading-4\" href=\"https:\/\/www.delveinsight.com\/blog\/tigit-inhibitor-landscape\/#TIGIT_Mechanisms_of_Action\" >TIGIT Mechanisms of Action<\/a><ul class='ez-toc-list-level-3' ><li class='ez-toc-heading-level-3'><a class=\"ez-toc-link ez-toc-heading-5\" href=\"https:\/\/www.delveinsight.com\/blog\/tigit-inhibitor-landscape\/#Cell-extrinsic_Mechanism\" >Cell-extrinsic Mechanism<\/a><\/li><li class='ez-toc-page-1 ez-toc-heading-level-3'><a class=\"ez-toc-link ez-toc-heading-6\" href=\"https:\/\/www.delveinsight.com\/blog\/tigit-inhibitor-landscape\/#Cell-intrinsic_Mechanisms\" >Cell-intrinsic Mechanisms<\/a><\/li><\/ul><\/li><li class='ez-toc-page-1 ez-toc-heading-level-2'><a class=\"ez-toc-link ez-toc-heading-7\" href=\"https:\/\/www.delveinsight.com\/blog\/tigit-inhibitor-landscape\/#The_Target_for_Cancer_Immunotherapy\" >The Target for Cancer Immunotherapy<\/a><\/li><li class='ez-toc-page-1 ez-toc-heading-level-2'><a class=\"ez-toc-link ez-toc-heading-8\" href=\"https:\/\/www.delveinsight.com\/blog\/tigit-inhibitor-landscape\/#Treatment_Landscape_Through_the_Lens_of_TIGIT_Inhibitors\" >Treatment Landscape Through the Lens of TIGIT Inhibitors<\/a><\/li><li class='ez-toc-page-1 ez-toc-heading-level-2'><a class=\"ez-toc-link ez-toc-heading-9\" href=\"https:\/\/www.delveinsight.com\/blog\/tigit-inhibitor-landscape\/#Whats_cooking_in_the_Lab\" >What\u2019s cooking in the Lab?<\/a><\/li><li class='ez-toc-page-1 ez-toc-heading-level-2'><a class=\"ez-toc-link ez-toc-heading-10\" href=\"https:\/\/www.delveinsight.com\/blog\/tigit-inhibitor-landscape\/#Conclusion\" >Conclusion<\/a><\/li><\/ul><\/nav><\/div>\n\n<p class=\"has-drop-cap\">T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is a relatively new immunological checkpoint that has been studied as a potential immunotherapeutic target. TIGIT is a transmembrane glycoprotein receptor containing an Ig-like V-type domain in its cytoplasmic domain and an ITIM in its extracellular domain. It&#8217;s found in activated and memory T cells, as well as NK cells and Tregs. CD155 (PVR: poliovirus receptor) and CD112 (PVRL2, nectin-2) bind to each other on APCs, preventing maturation and conferring a tolerogenic phenotype. Numerous clinical trials on TIGIT-blockade in cancer have been initiated, predominantly combination treatments.&nbsp;<\/p>\n\n\n\n<h2 class=\"wp-block-heading\" id=\"h-tigit-structure\"><span class=\"ez-toc-section\" id=\"TIGIT_Structure\"><\/span>TIGIT Structure<span class=\"ez-toc-section-end\"><\/span><\/h2>\n\n\n\n<p>TIGIT is a member of a growing family of PVR-like proteins. It was independently discovered in 2009 by three groups through genome-wide analysis aiming to identify proteins containing domain structures typical for immunomodulatory receptors. TIGIT consists of one extracellular immunoglobulin variable domain, a type I transmembrane domain, and a short intracellular domain with one immunoreceptor tyrosine-based inhibitory motif (ITIM) and one immunoglobulin tyrosine tail (ITT)-like motif.<\/p>\n\n\n\n<figure class=\"wp-block-image size-full\"><img decoding=\"async\" width=\"728\" height=\"386\" src=\"https:\/\/assets.delveinsight.com\/blog\/wp-content\/uploads\/2022\/02\/10184344\/tigit-structure-and-pathway.jpg\" alt=\"t-cell-immunoglobulin-and-itim-domain-dnax-accessory-molecule-1-tigit-dnam-1-pathway\" class=\"wp-image-16007\" srcset=\"https:\/\/assets.delveinsight.com\/blog\/wp-content\/uploads\/2022\/02\/10184344\/tigit-structure-and-pathway.jpg 728w, https:\/\/assets.delveinsight.com\/blog\/wp-content\/uploads\/2022\/02\/10184344\/tigit-structure-and-pathway-300x159.jpg 300w, https:\/\/assets.delveinsight.com\/blog\/wp-content\/uploads\/2022\/02\/10184344\/tigit-structure-and-pathway-150x80.jpg 150w\" sizes=\"(max-width: 728px) 100vw, 728px\" \/><figcaption><strong><strong>T cell Immunoglobulin and ITIM Domain\/DNAX Accessory Molecule-1 (TIGIT\/DNAM-1) Pathway<\/strong><\/strong><\/figcaption><\/figure>\n\n\n\n<h2 class=\"wp-block-heading\" id=\"h-tigit-expression\"><span class=\"ez-toc-section\" id=\"TIGIT_Expression\"><\/span>TIGIT Expression<span class=\"ez-toc-section-end\"><\/span><\/h2>\n\n\n\n<p>TIGIT is expressed on CD4+ T cells, CD8+ T cells, and Tregs in both mice and humans. <a href=\"https:\/\/www.delveinsight.com\/report-store\/tigit-inhibitors-pipeline-insight\">TIGIT expression<\/a> is normally low in naive cells, but T and NK cells have been shown to up-regulate TIGIT after activation. As a result, Tregs, memory and activated T cells, and NK cells have the highest TIGIT expression in naive mice and healthy individuals.<\/p>\n\n\n\n<p class=\"has-text-align-center\"><strong>Cells Expressing TIGIT Receptors and Ligands<\/strong><\/p>\n\n\n\n<div class=\"visualizer-front-container\" id=\"chart_wrapper_visualizer-14586-667007628\"><style type=\"text\/css\" name=\"visualizer-custom-css\" id=\"customcss-visualizer-14586\">.locker,.locker-loader{position:absolute;top:0;left:0;width:100%;height:100%}.locker{z-index:1000;opacity:.8;background-color:#fff;-ms-filter:\"progid:DXImageTransform.Microsoft.Alpha(Opacity=80)\";filter:alpha(opacity=80)}.locker-loader{z-index:1001;background:url(https:\/\/www.delveinsight.com\/blog\/wp-content\/plugins\/visualizer\/images\/ajax-loader.gif) no-repeat center center}.dt-button{display:none!important}.visualizer-front-container.visualizer-lazy-render{content-visibility: auto;}.google-visualization-controls-categoryfilter label.google-visualization-controls-label {vertical-align: middle;}.google-visualization-controls-categoryfilter li.goog-inline-block {margin: 0 0.2em;}.google-visualization-controls-categoryfilter li {padding: 0 0.2em;}.visualizer-front-container .dataTables_scrollHeadInner{margin: 0 auto;}<\/style><div id=\"visualizer-14586-667007628\" class=\"visualizer-front  visualizer-front-14586\"><\/div><!-- Not showing structured data for chart 14586 because description is empty --><\/div>\n\n\n\n<h2 class=\"wp-block-heading\"><span class=\"ez-toc-section\" id=\"TIGITs_Ligands\"><\/span>TIGIT\u2019s Ligands<span class=\"ez-toc-section-end\"><\/span><\/h2>\n\n\n\n<p>TIGIT has three ligands: CD155, CD112, and CD113, which are all members of the nectin and NECL family of molecules. This family includes cell surface molecules that mediate cell adhesion, cell polarity, and tissue organisation, as well as herpes and poliovirus receptors. <a href=\"https:\/\/www.delveinsight.com\/report-store\/tigit-inhibitors-pipeline-insight\">TIGIT&#8217;s major ligand<\/a> is CD155, which is found in both humans and mice. TIGIT and CD155 form homodimers and heterotetramers after ligand-receptor contact, according to crystal structure studies. TIGIT has a lower affinity for CD112 and CD113 than CD155.<\/p>\n\n\n\n<h2 class=\"wp-block-heading\"><span class=\"ez-toc-section\" id=\"TIGIT_Mechanisms_of_Action\"><\/span>TIGIT Mechanisms of Action<span class=\"ez-toc-section-end\"><\/span><\/h2>\n\n\n\n<p>TIGIT-mediated inhibitor of effector T cells and NK cells has been linked to a variety of processes. TIGIT can function either cell-extrinsically as a CD155 ligand or cell-intrinsically by interfering with DNAM-1 co-stimulation or directly providing inhibitory signals to effector cells. It&#8217;s unknown whether all of these processes are active in every TIGIT-expressing cell or if the TIGIT method of action varies between CD4+ T cells, CD8+ T cells, and NK cells. TIGIT also improves Treg suppressive capabilities when expressed on Tregs, potentially inhibiting a wide range of immune cells.<\/p>\n\n\n\n<figure class=\"wp-block-image size-full\"><img decoding=\"async\" width=\"559\" height=\"273\" src=\"https:\/\/assets.delveinsight.com\/blog\/wp-content\/uploads\/2022\/02\/10182553\/tigit-mechanism-of-action.jpg\" alt=\"t-cell-immunoglobulin-and-itim-domain-tigit-mechanism-of-action-tigit\" class=\"wp-image-15992\" srcset=\"https:\/\/assets.delveinsight.com\/blog\/wp-content\/uploads\/2022\/02\/10182553\/tigit-mechanism-of-action.jpg 559w, https:\/\/assets.delveinsight.com\/blog\/wp-content\/uploads\/2022\/02\/10182553\/tigit-mechanism-of-action-300x147.jpg 300w, https:\/\/assets.delveinsight.com\/blog\/wp-content\/uploads\/2022\/02\/10182553\/tigit-mechanism-of-action-150x73.jpg 150w\" sizes=\"(max-width: 559px) 100vw, 559px\" \/><figcaption><strong>T cell Immunoglobulin and ITIM Domain (TIGIT) Mechanism of Action. (TIGIT has been reported to inhibit T cells and natural killer (NK) cells via several mechanisms)<\/strong><\/figcaption><\/figure>\n\n\n\n<h3 class=\"wp-block-heading\"><span class=\"ez-toc-section\" id=\"Cell-extrinsic_Mechanism\"><\/span><strong>Cell-extrinsic Mechanism<\/strong><span class=\"ez-toc-section-end\"><\/span><\/h3>\n\n\n\n<p>Based on the discovery that neither TIGIT-specific small interfering RNA (siRNA) nor anti-TIGIT mAbs impacted human memory CD4+ T cell responses to antiCD3 stimulation, early investigations suggested a cell-extrinsic mechanism. Anti-TIGIT mAbs, on the other hand, boosted T cell proliferation and IFN- production when T cells were cultivated with autologous CD11c+ DCs. Antigen-presenting cells (APCs) such as DCs are essential for priming T cell responses. The sort of DCs used and their maturity stage determine the quality of the T cell response elicited. TIGIT&#8217;s interaction with CD155 regulated DC cytokine production, according to Yu et al. CD155 signalling in human monocyte-derived DCs boosted IL-10 secretion while decreasing proinflammatory cytokine IL-12 secretion after TIGIT ligation. TIGIT\u2013CD155 interactions appear to promote tolerogenic DCs that suppress T cell responses, according to these findings.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><span class=\"ez-toc-section\" id=\"Cell-intrinsic_Mechanisms\"><\/span><strong>Cell-intrinsic Mechanisms<\/strong><span class=\"ez-toc-section-end\"><\/span><\/h3>\n\n\n\n<p>TIGIT suppresses T cell activities in a cell-intrinsic manner, in addition to its activity as a regulator of DCs and macrophages. In the absence of APCs, agonistic anti-TIGIT mAbs have been demonstrated to suppress anti-CD3\/anti-CD28 mAb-mediated human and mouse T cell proliferation and cytokine generation. Furthermore, melanoma cells expressing a shortened variant of CD155 reduced CD8+ T cell IFN- production comparable to cells expressing wild-type CD155, according to a recent study. TIGIT\u2013CD155 contact can decrease T cell functions without CD155 downstream signalling, indicating that TIGIT\u2013CD155 interaction can inhibit T cell functions without CD155 downstream signalling. Given TIGIT&#8217;s strong affinity for CD155, the cell-intrinsic mechanism of action was speculated to be TIGIT inhibiting T cells by out-competing DNAM-1 for CD155 binding.<\/p>\n\n\n\n<h2 class=\"wp-block-heading\"><span class=\"ez-toc-section\" id=\"The_Target_for_Cancer_Immunotherapy\"><\/span>The Target for Cancer Immunotherapy<span class=\"ez-toc-section-end\"><\/span><\/h2>\n\n\n\n<p>Even before the discovery of TIGIT, its ligands were known to be upregulated on the surface tumour cell surface. Expression of the nectin family of proteins and their role in cell adhesion and survival was reported in tumors from the epithelial origin, such as non-small cell lung cancer, colon cancer, and metastatic neuroblastoma, and also tumors from the hematopoietic origin, such as myeloid leukaemia. High expression of CD155 was shown to be an independent prognostic marker and predictor of poor clinical outcomes in breast cancer patients. The recently discovered ligand for TIGIT, nectin 4, was shown to be overexpressed in breast, bladder, lung, and pancreatic cancers. On the other hand, TIGIT expression was also reported to be upregulated on lymphocytes in the tumour microenvironment. Studies showed TIGIT expression on CD8+, CD4+ T cells, and NK cells paralleled to that of PD-1 in the hepatocellular, lung, and colorectal cancers and in Hodgkin\u2019s lymphoma. The potential of targeting TIGIT was shown using in-vivo mouse models for cancers and chronic viral infection. Researchers showed that blockade of TIGIT along with PD-L1 enhanced CD8+ T-cell effector function and tumour and viral clearance. Studies in tumour-bearing Tigit+\/+ and Tigit\u2212\/\u2212 mice demonstrated increased TIGIT expression on tumour-infiltrating lymphocytes and lack of TIGIT in Tregs to be critical for immune suppression in the tumour microenvironment. Administration of monoclonal antibodies against TIGIT was shown to increase the survival rate in mouse models for ovarian cancer. A study found that the anti-TIGIT antibody treatment reduced CD4+ Tregs but did not affect the proportion of CD4+ T-helper cells, CD8+ T cells, or NK cells.&nbsp;<\/p>\n\n\n\n<p class=\"has-text-align-center\"><strong>Collaborations Assessment- Licensing \/ Partnering \/ Funding<\/strong><\/p>\n\n\n\n<div class=\"visualizer-front-container\" id=\"chart_wrapper_visualizer-14592-995860366\"><style type=\"text\/css\" name=\"visualizer-custom-css\" id=\"customcss-visualizer-14592\">.locker,.locker-loader{position:absolute;top:0;left:0;width:100%;height:100%}.locker{z-index:1000;opacity:.8;background-color:#fff;-ms-filter:\"progid:DXImageTransform.Microsoft.Alpha(Opacity=80)\";filter:alpha(opacity=80)}.locker-loader{z-index:1001;background:url(https:\/\/www.delveinsight.com\/blog\/wp-content\/plugins\/visualizer\/images\/ajax-loader.gif) no-repeat center center}.dt-button{display:none!important}.visualizer-front-container.visualizer-lazy-render{content-visibility: auto;}.google-visualization-controls-categoryfilter label.google-visualization-controls-label {vertical-align: middle;}.google-visualization-controls-categoryfilter li.goog-inline-block {margin: 0 0.2em;}.google-visualization-controls-categoryfilter li {padding: 0 0.2em;}.visualizer-front-container .dataTables_scrollHeadInner{margin: 0 auto;}<\/style><div id=\"visualizer-14592-995860366\" class=\"visualizer-front  visualizer-front-14592\"><\/div><!-- Not showing structured data for chart 14592 because description is empty --><\/div>\n\n\n\n<p><\/p>\n\n\n\n<p>Recent research has identified TIGIT as a promising <a href=\"https:\/\/www.delveinsight.com\/blog\/immune-checkpoint-activators-dynamic-therapeutic-targets\">emerging immune checkpoint<\/a> target. TIGIT indirectly suppresses T-cell activation and is expressed on multiple types of immune cells, including regulatory T (Treg) cells, activated T cells, and natural killer (NK) cells. TIGIT is upregulated in T cells and NK cells after ligand binding, inhibiting these cells&#8217; ability to kill tumour cells. Increased TIGIT expression is also associated with advanced disease and poor survival outcomes. Additionally, increased TIGIT expression after treatment is associated with disease recurrence. TIGIT and its coreceptors, including CD226 and CD96, interact with a group of ligands expressed on tumour cells: nectins and nectin-like molecules, including poliovirus receptor (PVR), the main TIGIT ligand. PVR ligands binding to TIGIT suppresses the antitumor immune response of the TIGIT-expressing cell; in contrast, ligand binding to CD226 triggers immune cell activation. Thus, TIGIT and CD226 oppose each other to regulate tumour immunity. Anti-TIGIT therapy is presumed to invigorate immune function and enhance the activity of T cells and NK cells. ( <strong>Explore more about <\/strong><a href=\"https:\/\/www.delveinsight.com\/report-store\/natural-killer-cell-therapies-competitive-landscape-technology-and-pipeline-analysis\"><strong><em>NK cells in cancer<\/em><\/strong><\/a>)<\/p>\n\n\n\n<h2 class=\"wp-block-heading\"><span class=\"ez-toc-section\" id=\"Treatment_Landscape_Through_the_Lens_of_TIGIT_Inhibitors\"><\/span>Treatment Landscape Through the Lens of TIGIT Inhibitors<span class=\"ez-toc-section-end\"><\/span><\/h2>\n\n\n\n<p>One avenue of investigation in recent years has been immune-oncology, which encourages the human body to make use of its natural defences to combat cancer. The activation of immune cells against tumors is seen to be an extremely promising approach, as it allows the efficient eradication of existing tumour cells through the generation of long-term protective immune memory. Moreover, unlike common <a href=\"https:\/\/www.delveinsight.com\/blog\/oncology\">oncologic treatments<\/a>, immune activation is associated with targeted effects and lower toxicity and may lead to extremely long recurrence-free events due to the generation of this protective memory.<\/p>\n\n\n\n<p>There have been quite exciting developments in the treatment development landscape involving the <a href=\"https:\/\/www.delveinsight.com\/report-store\/tigit-inhibitors-pipeline-insight\">TIGIT Inhibitor-based therapies<\/a>. <strong>The drugs which are under development are being investigated in trials both as monotherapy as well as in combination with some other drugs; however, the majority of the TIGIT inhibitor drugs are being developed as combination therapy.<\/strong>&nbsp;<\/p>\n\n\n\n<figure class=\"wp-block-image size-full\"><img decoding=\"async\" width=\"823\" height=\"355\" src=\"https:\/\/assets.delveinsight.com\/blog\/wp-content\/uploads\/2022\/02\/10182636\/key-companies-in-the-tigit-inhibitors-market.jpg\" alt=\"key-companies-in-the-tigit-inhibitors-market\" class=\"wp-image-15993\" srcset=\"https:\/\/assets.delveinsight.com\/blog\/wp-content\/uploads\/2022\/02\/10182636\/key-companies-in-the-tigit-inhibitors-market.jpg 823w, https:\/\/assets.delveinsight.com\/blog\/wp-content\/uploads\/2022\/02\/10182636\/key-companies-in-the-tigit-inhibitors-market-300x129.jpg 300w, https:\/\/assets.delveinsight.com\/blog\/wp-content\/uploads\/2022\/02\/10182636\/key-companies-in-the-tigit-inhibitors-market-150x65.jpg 150w, https:\/\/assets.delveinsight.com\/blog\/wp-content\/uploads\/2022\/02\/10182636\/key-companies-in-the-tigit-inhibitors-market-768x331.jpg 768w\" sizes=\"(max-width: 823px) 100vw, 823px\" \/><figcaption>Leading Players in the TIGIT Inhibitors Domain<\/figcaption><\/figure>\n\n\n\n<p>Some of the notable ones include therapies being developed by <strong>Bristol Myers Squibb<\/strong>,<strong> Roche<\/strong>, <strong>GlaxoSmithKline <\/strong>and<strong> iTeos Therapeutics<\/strong>,<strong> Gilead<\/strong>, and<strong> AstraZeneca<\/strong>, to name a few.&nbsp;<\/p>\n\n\n\n<p>The development milestones have been discussed below, which highlight the activity around this target, showcasing great potential in the cancer immunotherapy area.<\/p>\n\n\n\n<div class=\"visualizer-front-container\" id=\"chart_wrapper_visualizer-14599-217797083\"><style type=\"text\/css\" name=\"visualizer-custom-css\" id=\"customcss-visualizer-14599\">.locker,.locker-loader{position:absolute;top:0;left:0;width:100%;height:100%}.locker{z-index:1000;opacity:.8;background-color:#fff;-ms-filter:\"progid:DXImageTransform.Microsoft.Alpha(Opacity=80)\";filter:alpha(opacity=80)}.locker-loader{z-index:1001;background:url(https:\/\/www.delveinsight.com\/blog\/wp-content\/plugins\/visualizer\/images\/ajax-loader.gif) no-repeat center center}.dt-button{display:none!important}.visualizer-front-container.visualizer-lazy-render{content-visibility: auto;}.google-visualization-controls-categoryfilter label.google-visualization-controls-label {vertical-align: middle;}.google-visualization-controls-categoryfilter li.goog-inline-block {margin: 0 0.2em;}.google-visualization-controls-categoryfilter li {padding: 0 0.2em;}.visualizer-front-container .dataTables_scrollHeadInner{margin: 0 auto;}<\/style><div id=\"visualizer-14599-217797083\" class=\"visualizer-front  visualizer-front-14599\"><\/div><!-- Not showing structured data for chart 14599 because description is empty --><\/div>\n\n\n\n<p>Just some months before, in January 2021, <strong>Roche<\/strong> <strong>(Genentech)<\/strong> announced that <a href=\"https:\/\/www.delveinsight.com\/asco-conference\/article\/NCT03563716\"><strong>tiragolumab<\/strong><\/a>, novel cancer immunotherapy designed to bind to TIGIT, received Breakthrough Therapy Designation (BTD) by the US Food and Drug Administration (FDA), in combination with Tecentriq (atezolizumab) for metastatic non-small cell lung cancer (NSCLC) treatment as a first-line in people whose tumors have high PD-L1 expression with no EGFR or ALK genomic tumour aberrations. Tiragolumab is the first anti-TIGIT molecule to be granted BTD from the FDA, and the designation is based on randomized data from the phase II CITYSCAPE trial. CITYSCAPE provides the first evidence that targeting both immune inhibitory receptors, TIGIT and PD-L1, may enhance anti-tumour activity by potentially amplifying the immune response.<\/p>\n\n\n\n<p><strong>Domvanalimab<\/strong>, an advanced anti-TIGIT candidate, is an Fc-silent investigational monoclonal antibody that blocks TIGIT and has demonstrated complete receptor coverage on all TIGIT-expressing peripheral leukocytes. This investigational medicine is designed to treat solid tumors because the silent Fc domain is believed to eliminate the potential for depletion of TIGIT-bearing immune cells, which are critical for anti-tumour immune activity. Domvanalimab is currently being evaluated in an ongoing Phase III registrational study in combination with <strong>zimberelimab<\/strong>, an anti-PD-1 monoclonal antibody in first-line locally advanced or metastatic, PD-L1&gt;50% non-small cell lung cancer.<\/p>\n\n\n\n<figure class=\"wp-block-image size-large\"><a href=\"https:\/\/www.delveinsight.com\/report-store\/tigit-inhibitors-pipeline-insight\"><img decoding=\"async\" src=\"https:\/\/assets.delveinsight.com\/blog\/wp-content\/uploads\/2021\/12\/06183228\/TIGIT-Inhibitors-Landscape.png\" alt=\"tigit-inhibitors-landscape\"\/><\/a><\/figure>\n\n\n\n<p>Most recently, in August 2021, Compugen announced that a bispecific antibody of AstraZeneca derived from COM902, Compugen&#8217;s high-affinity anti-TIGIT antibody, will advance into clinical development. AstraZeneca plans to initiate a Phase I\/II study evaluating AZD2936, a TIGIT\/PD-1 bispecific antibody, in patients with advanced or metastatic non-small cell lung cancer. Some other notable TIGIT inhibitors being developed include<strong> Ociperlimab (BGB-A1217) <\/strong>and<strong> MK-7684A. Ociperlimab <\/strong>is an investigational humanized monoclonal antibody designed to bind to TIGIT with high specificity and affinity. Ociperlimab is one of the most advanced anti-TIGIT antibodies in development with an intact IgG Fc binding region for optimal antibody-mediated anti-tumour activity.<strong> MK-7684A<\/strong> is a formulation of Vibostolimab\/pembrolizumab which is being developed by Merck and is currently in Phase III stage of development for <a href=\"https:\/\/www.delveinsight.com\/report-store\/non-small-cell-lung-cancer-nsclc-pipeline-insight\">Non-small cell lung cancer treatment<\/a> and other indications in lower phases. <\/p>\n\n\n\n<p class=\"has-text-align-center\"><strong>The Pipeline Scenario of TIGIT Inhibitors<\/strong><\/p>\n\n\n\n<div class=\"visualizer-front-container\" id=\"chart_wrapper_visualizer-14590-1182654603\"><style type=\"text\/css\" name=\"visualizer-custom-css\" id=\"customcss-visualizer-14590\">.locker,.locker-loader{position:absolute;top:0;left:0;width:100%;height:100%}.locker{z-index:1000;opacity:.8;background-color:#fff;-ms-filter:\"progid:DXImageTransform.Microsoft.Alpha(Opacity=80)\";filter:alpha(opacity=80)}.locker-loader{z-index:1001;background:url(https:\/\/www.delveinsight.com\/blog\/wp-content\/plugins\/visualizer\/images\/ajax-loader.gif) no-repeat center center}.dt-button{display:none!important}.visualizer-front-container.visualizer-lazy-render{content-visibility: auto;}.google-visualization-controls-categoryfilter label.google-visualization-controls-label {vertical-align: middle;}.google-visualization-controls-categoryfilter li.goog-inline-block {margin: 0 0.2em;}.google-visualization-controls-categoryfilter li {padding: 0 0.2em;}.visualizer-front-container .dataTables_scrollHeadInner{margin: 0 auto;}<\/style><div id=\"visualizer-14590-1182654603\" class=\"visualizer-front  visualizer-front-14590\"><\/div><!-- Not showing structured data for chart 14590 because description is empty --><\/div>\n\n\n\n<h2 class=\"wp-block-heading\"><span class=\"ez-toc-section\" id=\"Whats_cooking_in_the_Lab\"><\/span><strong>What\u2019s cooking in the Lab?<\/strong><span class=\"ez-toc-section-end\"><\/span><\/h2>\n\n\n\n<p>Apart from the clinical assets in development, there have been some interesting advancements from the preclinical\/discovery aspect as well. <strong>Zhang et al<\/strong>. reported that early treatment with anti-TIGIT mAbs (i.e. started before the tumour was established) delayed the growth of CT26 subcutaneous tumors and methylcholanthrene (MCA) &#8211; induced fibrocarcinomas. The same group showed that anti-TIGIT mAbs protected mice against 4T1 or B16 experimental metastasis. Interestingly, Zhang et al. proposed that NK cells were involved in the protection observed following TIGIT-blockade in all these different models. Similarly, we found that blocking TIGIT significantly decreased tumour burden in an aggressive mouse myeloma model (Vk12653) and increased survival in two additional mouse myeloma models, Vk12598 and 5TGM1.<\/p>\n\n\n\n<p>\u201cTIGIT inhibits T-cell activation,\u201d <strong>Vijay K. Kuchroo<\/strong>, DVM, PhD, the Samuel L. Wasserstrom Professor of Neurology at Harvard Medical School and a senior scientist in neurology at Brigham and Women\u2019s Hospital in Boston, Massachusetts, who has studied TIGIT for the past 15 years, said in an interview with&nbsp;Targeted Therapies in Oncology. \u201cOur data suggest that [inhibiting] it cooperates well with PD-1 blockade.\u201d Tumors use the inhibitory TIGIT pathway to avoid attack by the immune system. Thus, therapeutic agents that inhibit TIGIT signalling by, for example, disrupting ligand binding promote the ability of T cells to proliferate and attack tumour cells.<\/p>\n\n\n\n<p class=\"has-text-align-center\"><strong>Summary of Key Findings<\/strong><\/p>\n\n\n\n<div class=\"visualizer-front-container\" id=\"chart_wrapper_visualizer-14594-277070090\"><style type=\"text\/css\" name=\"visualizer-custom-css\" id=\"customcss-visualizer-14594\">.locker,.locker-loader{position:absolute;top:0;left:0;width:100%;height:100%}.locker{z-index:1000;opacity:.8;background-color:#fff;-ms-filter:\"progid:DXImageTransform.Microsoft.Alpha(Opacity=80)\";filter:alpha(opacity=80)}.locker-loader{z-index:1001;background:url(https:\/\/www.delveinsight.com\/blog\/wp-content\/plugins\/visualizer\/images\/ajax-loader.gif) no-repeat center center}.dt-button{display:none!important}.visualizer-front-container.visualizer-lazy-render{content-visibility: auto;}.google-visualization-controls-categoryfilter label.google-visualization-controls-label {vertical-align: middle;}.google-visualization-controls-categoryfilter li.goog-inline-block {margin: 0 0.2em;}.google-visualization-controls-categoryfilter li {padding: 0 0.2em;}.visualizer-front-container .dataTables_scrollHeadInner{margin: 0 auto;}<\/style><div id=\"visualizer-14594-277070090\" class=\"visualizer-front  visualizer-front-14594\"><\/div><!-- Not showing structured data for chart 14594 because title is empty --><\/div>\n\n\n\n<h2 class=\"wp-block-heading\"><span class=\"ez-toc-section\" id=\"Conclusion\"><\/span><strong>Conclusion<\/strong><span class=\"ez-toc-section-end\"><\/span><\/h2>\n\n\n\n<p>TIGIT has emerged as an important immune checkpoint capable of inhibiting each step of the cancer immunity circle due to its broad expression on lymphocytes. Tumour antigen release by NK cells may be prevented by TIGIT, impairing T cell priming by DCs or inhibiting cancer cell killing by CD8+ T cells. When combined with other immunotherapies, TIGIT targeting is likely to be the most efficient.&nbsp;<\/p>\n\n\n\n<p>A significant number of preclinical studies indicated that TIGIT would constitute a suitable target for cancer patients and the results of six ongoing clinical trials are eagerly awaited. In pre-clinical studies, targeting TIGIT together with the <a href=\"https:\/\/www.delveinsight.com\/blog\/pd-1-and-pdl-1-immune-check-point-inhibitors-a-prodigious-revolution-in-cancer-treatment\">PD-1\/PD-L1 pathway<\/a> demonstrated superior tumour suppression compared to monotherapy. TIGIT has also been found to regulate antiviral responses and perhaps impair immune control to human immunodeficiency virus.&nbsp; Combination therapy using anti-TIGIT and anti-PD-1 antibodies further conferred a greater survival benefit in all anti-TIGIT treatment schedules, implying a synergistic mechanism following interruption of the two inhibitory checkpoints. This improvement in therapeutic efficacy following dual blockade of the TIGIT and PD-1 pathways has been demonstrated in several murine models.&nbsp;<\/p>\n\n\n\n<p>The design of optimized combination strategies for TIGIT blockade in cancer patients is being facilitated with the increasing understanding of TIGIT-mediated regulation of immune responses and will also help to treat other chronic diseases with the development of TIGIT- targeting therapies. Thus, TIGIT inhibitors are creating great inroads in the Immuno-oncology space by providing better opportunities, as late-stage clinical research is evaluating this inhibitor in combination with PD\/L-1 inhibitors in high PD-L1, refractory PD-1, and adjuvant settings, especially in NSCLC patients.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is a relatively new immunological checkpoint that has been studied as a potential immunotherapeutic target. TIGIT is a transmembrane glycoprotein receptor containing an Ig-like V-type domain in its cytoplasmic domain and an ITIM in its extracellular domain. It&#8217;s found in activated and memory T cells, as well [&hellip;]<\/p>\n","protected":false},"author":14,"featured_media":15994,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"_editorskit_title_hidden":false,"_editorskit_reading_time":0,"_editorskit_is_block_options_detached":false,"_editorskit_block_options_position":"{}","advgb_blocks_editor_width":"","advgb_blocks_columns_visual_guide":"","footnotes":""},"categories":[17],"tags":[18911,1409,983,1111,457,17396,18910,18907,18909,18908],"industry":[17225],"therapeutic_areas":[17228],"class_list":["post-14620","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-articles","tag-cancer-immunotherapy","tag-immune-checkpoints","tag-nk-cells","tag-nsclc","tag-pd-1pdl-1","tag-pd1","tag-tigit-expression","tag-tigit-inhibitors","tag-tigit-inhibitors-drugs","tag-tigit-inhibitors-therapies","industry-pharmaceutical","therapeutic_areas-oncology"],"acf":[],"yoast_head":"<!-- This site is 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class=\"advgb-post-tax-term\">PD-1\/PDL-1<\/a>","<a href=\"https:\/\/www.delveinsight.com\/blog\/articles\/\" class=\"advgb-post-tax-term\">PD1<\/a>","<a href=\"https:\/\/www.delveinsight.com\/blog\/articles\/\" class=\"advgb-post-tax-term\">TIGIT Expression<\/a>","<a href=\"https:\/\/www.delveinsight.com\/blog\/articles\/\" class=\"advgb-post-tax-term\">TIGIT Inhibitors<\/a>","<a href=\"https:\/\/www.delveinsight.com\/blog\/articles\/\" class=\"advgb-post-tax-term\">TIGIT Inhibitors Drugs<\/a>","<a href=\"https:\/\/www.delveinsight.com\/blog\/articles\/\" class=\"advgb-post-tax-term\">TIGIT Inhibitors Therapies<\/a>"],"unlinked":["<span class=\"advgb-post-tax-term\">Cancer immunotherapy<\/span>","<span class=\"advgb-post-tax-term\">Immune checkpoints<\/span>","<span class=\"advgb-post-tax-term\">NK Cells<\/span>","<span class=\"advgb-post-tax-term\">NSCLC<\/span>","<span class=\"advgb-post-tax-term\">PD-1\/PDL-1<\/span>","<span class=\"advgb-post-tax-term\">PD1<\/span>","<span class=\"advgb-post-tax-term\">TIGIT Expression<\/span>","<span class=\"advgb-post-tax-term\">TIGIT Inhibitors<\/span>","<span class=\"advgb-post-tax-term\">TIGIT Inhibitors Drugs<\/span>","<span class=\"advgb-post-tax-term\">TIGIT Inhibitors Therapies<\/span>"]}},"comment_count":"0","relative_dates":{"created":"Posted 4 years ago","modified":"Updated 4 years ago"},"absolute_dates":{"created":"Posted on Dec 6, 2021","modified":"Updated on Feb 10, 2022"},"absolute_dates_time":{"created":"Posted on Dec 6, 2021 7:10 pm","modified":"Updated on Feb 10, 2022 6:43 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