T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is one of the most recent immune checkpoints to be investigated as an immunotherapeutic target. TIGIT is a transmembrane glycoprotein receptor and consists of a short extracellular domain containing one extracellular IgV domain fused with a type 1 transmembrane region and two immune receptor tyrosine-based inhibitory motifs (ITIM). It is expressed on activated and memory T cells, NK cells, and Tregs.
The TIGIT IgV domain possesses distinctive (V/I)(S/T)Q, AX6G, and T(F/Y)PX1G submotifs that mediate a ‘lock and key’ trans-interaction with cis-homodimers of PVR. TIGIT and its ligands, PVR and PVR-L2 comprise a novel immune checkpoint which blocks T-cells from attacking tumor cells and is similar in structure and function to the inhibitory protein PD-1.
Fig.1 TIGIT, CD226, CD96, and CD112R are expressed on activated T cells and NK cells.
TIGIT is expressed on multiple immune cell types, with potentially different functions on each. Immune activation of TIGIT-expressing cytotoxic T cells and natural killer (NK) cells is suppressed when TIGIT interacts with its ligands, PVR, or PVRL2, which are widely expressed on tumor cells. Expression of TIGIT on regulatory T cells enhances their immunosuppressive function, with indirect effects that include inhibition of proinflammatory cytokine production. TIGIT also directly suppresses the antitumor effector function of CD8 T cells.
Fig.2 Mechanisms of TIGIT inhibition of T cells in the TME.
TIGIT has explored its roles in cancer, autoimmunity, and viral immunity. TIGIT expressing CD8+ T cells are expanded and associated with clinical markers of HIV disease progression in a diverse group of HIV infected individuals. The pathway formed by TIGIT, CD96, and costimulatory receptor CD226 (DNAM-1) is analogous to the CD28/CTLA-4 pathway. TIGIT, along with LAG-3 and TIM-3, form a group of coinhibitory receptors considered to be the next generation of clinical cancer targets following the notable yet limited success of CTLA-4 and PD-1 inhibitors. Co-blockade of TIGIT and PD-1 pathways elicit tumor rejection in preclinical murine models.
Dual PD-1 and TIGIT blockade is promising combinatorial immunotherapy of cancer. The dual blockade enhances the proliferation and function of tumor antigen-specific CD8+ T cells and TILs isolated from patients with melanoma as compared with single blockade. The combination of atezolizumab (anti-PD-L1) and tiragolumab (anti-TIGIT) appears to provide superior clinical benefits as compared with PD-L1 blockade alone as first-line therapy for patients with PD-L1-positive non-small cell lung cancers.
Fig.3 Potential strategies for drug targeting
As a key inhibitor of anti-tumor responses, TIGIT can hinder multiple steps of the cancer immunity cycle. Pre-clinical studies indicated that TIGIT blockade may protect against various solid and haematological cancers. Several monoclonal antibodies that block the activity of TIGIT have been developed.
Tiragolumab (MTIG7192A) is a humanized IgG1 kappa monoclonal antibody that binds TIGIT to prevent its interaction with its ligand PVR. It was developed by Genentech/Roche.
Clinical Progress | |
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Phase III | Non-small cell lung cancer, Oesophageal cancer, Small cell lung cancer |
Phase I/II | Cervical cancer, Liver cancer |
Phase I | B-cell lymphoma, Multiple myeloma, Solid tumors |
Latest Event | |
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15 Oct 2020 | NCT04540211: Phase III clinical trials in patients with unresectable locally advanced, unresectable recurrent, or metastatic esophageal squamous cell carcinoma (first-line treatment) |
28 Sep 2020 | NCT04543617: Phase III clinical trials in patients with unresectable locally advanced esophageal squamous cell carcinoma (atezolizumab with or without tiragolumab) |
10 Aug 2018 | NCT03563716: Phase II clinical trials in chemotherapy-naïve patients with locally advanced or metastatic non-small cell lung cancer (combination with atezolizumab) |
AB154 is an anti-TIGIT humanized IgG1 monoclonal antibody with diminished FcgR binding.
Clinical Progress | |
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Phase II | Non-small cell lung cancer |
Phase I | Solid tumors |
Latest Event | |
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28 May 2020 | NCT04262856: Phase II clinical trials to evaluate the safety and efficacy front-line, non-small cell lung cancer (AB122 monotherapy, AB154 in combination with AB122, and AB154 in combination with AB122 and AB928) |
12 Sep 2018 | NCT03628677: Phase I clinical trials to evaluate the safety and tolerability in advanced malignancies (B154 Monotherapy and Combination Therapy) |
MK‐7684 is a humanized IgG1 antibody, which binds to TIGIT and blocks its interaction with CD155 or CD122.
Clinical Progress | |
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Phase II | Non-small cell lung cancer |
Phase I/II | Malignant melanoma |
Phase I | Solid tumors |
Latest Event | |
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21 Sep 2020 | Phase I efficacy and safety trials in Non-small cell lung cancer |
13 Dec 2016 | NCT02964013: Phase I clinical trials in metastatic solid cancers (monotherapy or combination with pembrolizumab) |
BMS-986207 is a human IgG1 (FcyR‐null) antibody that binds to TIGIT expressed on several types of immune cells. It was developed by Bristol-Myers Squibb.
Clinical Progress | |
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Phase II | Solid tumours |
Phase I/II | Multiple myeloma |
Latest Event | |
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08 Sep 2020 | Phase I/II clinical trials in Solid tumors (Combination therapy, Late-stage disease, Second-line therapy or greater) |
19 Aug 2020 | NCT02913313: Phase II clinical trials in Solid tumors (Monotherapy or combination with nivolumab) |
30 Jun 2020 | NCT04150965: Phase I/II clinical trials in multiple myeloma (combination elotuzumab, anti-LAG-3 (BMS-986016) and anti-TIGIT (BMS-986207)) |
ASP 8374 is a fully-human monoclonal IgG4 that was developed by Astellas Pharma and Potenza Therapeutics. ASP 8374 is an anti-human TIGIT antagonist with diminished FcgR binding.
Clinical Progress | |
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Phase I | Solid tumours |
Latest Event | |
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12 Jun 2020 | NCT03945253: Phase I clinical trial finished in Advanced Solid Tumors |
05 Aug 2019 | NCT03945253: Phase I clinical trial in Advanced Solid Tumors |
08 Sep 2017 | NCT03260322: Phase Ib clinical trial in Advanced Solid Tumors (Monotherapy or combination with pembrolizumab) |
| 15 Oct 2020 Tiragolumab NCT04540211: Phase III clinical trials in patients with unresectable locally advanced, unresectable recurrent, or metastatic esophageal squamous cell carcinoma (first-line treatment) |
| 28 Sep 2020 Tiragolumab NCT04543617: Phase III clinical trials in patients with unresectable locally advanced esophageal squamous cell carcinoma (atezolizumab with or without tiragolumab) |
| 21 Sep 2020 MK‐7684 Phase I efficacy and safety trials in Non-small cell lung cancer |
| 08 Sep 2018 BMS‐986207 Phase I/II clinical trials in Solid tumors (Combination therapy, Late-stage disease, Second-line therapy or greater) |
| 19 Aug 2020 BMS‐986207 NCT02913313: Phase II clinical trials in Solid tumors (Monotherapy or combination with nivolumab) |
| 30 Jun 2020 BMS‐986207 NCT04150965: Phase I/II clinical trials in multiple myeloma (combination elotuzumab, anti-LAG-3 (BMS-986016) and anti-TIGIT (BMS-986207)) |
| 12 Jun 2020 ASP8374 NCT03945253: Phase I clinical trial finished in Advanced Solid Tumors |
| 28 May 2020 AB154 NCT04262856: Phase II clinical trials to evaluate the safety and efficacy front-line, non-small cell lung cancer (AB122 monotherapy, AB154 in combination with AB122, and AB154 in combination with AB122 and AB928) |
| 12 Sep 2018 AB154 NCT03628677: Phase I clinical trials to evaluate the safety and tolerability in advanced malignancies (B154 Monotherapy and Combination Therapy) |
| 05 Aug 2019 ASP8374 NCT03945253: Phase I clinical trial in Advanced Solid Tumors |
| 10 Aug 2018 Tiragolumab NCT03563716: Phase II clinical trials in chemotherapy-naïve patients with locally advanced or metastatic non-small cell lung cancer (combination with atezolizumab) |
| 08 Sep 2017 ASP8374 NCT03260322: Phase Ib clinical trial in Advanced Solid Tumors (Monotherapy or combination with pembrolizumab) |
| 08 Sep 2017 ASP8374 NCT03260322: Phase Ib clinical trial in Advanced Solid Tumors (Monotherapy or combination with pembrolizumab) |
| 13 Dec 2016 MK‐7684 NCT02964013: Phase I clinical trials in metastatic solid cancers (monotherapy or combination with pembrolizumab) |