OVERVIEW

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.

TIGIT-01Fig.1 TIGIT, CD226, CD96, and CD112R are expressed on activated T cells and NK cells.

Action Mechanism

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.

TIGIT-02 Fig.2 Mechanisms of TIGIT inhibition of T cells in the TME.

Clinical Significance

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.

TIGIT-03 Fig.3 Potential strategies for drug targeting

Ongoing Clinical Trials

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+-

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
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
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+-

AB154 is an anti-TIGIT humanized IgG1 monoclonal antibody with diminished FcgR binding.

Clinical Progress
Phase II Non-small cell lung cancer
Phase I Solid tumors
Latest Event
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+-

MK‐7684 is a humanized IgG1 antibody, which binds to TIGIT and blocks its interaction with CD155 or CD122.

Clinical Progress
Phase II Non-small cell lung cancer
Phase I/II Malignant melanoma
Phase I Solid tumors
Latest Event
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+-

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
Phase II Solid tumours
Phase I/II Multiple myeloma
Latest Event
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))
ASP8374+-

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
Phase I Solid tumours
Latest Event
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)

Reference

  1. Manieri, N. A.; et al. TIGIT: a key inhibitor of the cancer immunity cycle. Trends in immunology. 38(1), 20-28.
  2. Chauvin, J. M.; et al.. TIGIT in cancer immunotherapy. Journal for Immunotherapy of Cancer. 2020, 8(2).
  3. Zheng, Q.; et al.. Immune checkpoint targeting TIGIT in hepatocellular carcinoma. American Journal of Translational Research. 2020, 12(7), 3212.
  4. Harjunpää, H.; et al.. TIGIT as an emerging immune checkpoint. Clinical & Experimental Immunology. 2020, 200(2), 108-119.
  5. Zheng, Q.; et al.. Immune checkpoint targeting TIGIT in hepatocellular carcinoma. American Journal of Translational Research. 2020, 12(7), 3212.
For research use only, not directly for clinical use.

Anti-TIGIT Antibody Search

TIME LINE

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)

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