An Emerging Immue Checkpoint Target: TIGIT

The 2020 meeting of the American Society of Clinical Oncology (ASCO) concluded just over a month ago. Due to the impact of the COVID-19 pandemic, the meeting was conducted virtually. The ASCO Annual Meeting, one of the largest clinical oncology conferences globally, operates as a platform for oncology professionals to exchange the latest advancements in the field of clinical oncology. This year, briefings around BCMA, TIGIT, CD47 as well as several other targets were shared.

Roche shared their data of the tiragolumab positive Phase II clinical trial, an anti-TIGIT monoclonal antibody, which attracted significant attention. Their result demonstrates a 67% decrease in the risk of deterioration or death caused by the disease (median PFS=not reached vs 3.9 months; HR=0.33, 95% CI: 0.15–0.72) with when compared with Tecentriq alone.

These positive results usher in the idea that blockade of TIGIT and PD-L1 may synergistically facilitate the reactivation of T-cells and strengthen NK cell anti-tumor activity.

TIGIT was originally detected in a genomic search for genes expressed particularly in T cells that possessed protein domain structures typical of potential inhibitory receptors. TIGIT satisfies the role of coinhibitory receptors to counteract the costimulatory role of CD226.

TIGIT contends with immunoactivator receptor CD226 (DNAM-1) for the same group of ligands: CD155 (PVR or poliovirus receptor) and CD112 (Nectin-2 or PVRL2). Both NK cells and T cells demonstrated the expression of TIGIT and it acts as a catalyst in their activation and maturation.

A: Expression and Interactions of PVR Family Members; B: Inhibition of the Cancer Immunity Cycle by TIGIT

Figure 1. A: Expression and Interactions of PVR Family Members; B: Inhibition of the Cancer Immunity Cycle by TIGIT.

Emergent studies have revealed that blockade of TIGIT could have the capacity to supplement existing immunotherapies. TIGIT has shown excellent potentiality in preclinical models as a novel target for cancer immunotherapy and may work synergistically to broaden the activity of accepted checkpoint inhibitors, like anti-CTLA-4, anti-PD-1, etc. According to the record of the FDA, there are currently around 20 clinical trial studies focused on the target TIGIT.

Table 1. Selected TIGIT Targeted Research Summary.

Roche has commenced its Phase III clinical trial of anti-TIGIT antibody tiragolumab. Besides Roche, there are several companies in the following suit. The first to get its NDA approved from CFDA is Innovent Bio for its TIGIT antibody IBI939. This antibody can directly merge with TIGIT to alleviate the exhaustion of T cells and NK cells, therefore, fostering the anti-tumor effect. Meanwhile, it is anticipated to synergistically increase the anti-tumor activity of PD-1/PD-L1 antibody drugs.

BeiGene has started a Phase 1a/1b clinical trial of BGB-A1217 in combination with tislelizumab for advanced solid tumors in China and Australia. As an increasing number of pharmaceutical companies join this competition, advancements in TIGIT targeted antibodies will become a trend in the near future.

ACROBiosystems has prepared a series of TIGIT recombinant proteins to facilitate the progression of antibodies and the screening of inhibitors. The products are certified as a homodimer by MALS and are appropriate for numerous applications during the drug development process.

Assay data

Homodimer verified by MALS

The purity of Human TIGIT Protein, His Tag (Cat. No. TIT-H52H3) was more than 90% and around 30-45 kDa verified by SEC-MALS.

Figure 1. The purity of Human TIGIT Protein, His Tag (Cat. No. TIT-H52H3) was more than 90% and around 30-45 kDa verified by SEC-MALS.

Application in different phases of drug development

Immobilized Human TIGIT, His Tag (Cat. No. TIT-H52H3) at 2 μg/mL (100 μL/well) can bind Human CD155, Fc Tag (Cat. No. CD5-H5251) with a linear range of 8-128 ng/mL.

Figure 2. Immobilized Human TIGIT, His Tag (Cat. No. TIT-H52H3) at 2 μg/mL (100 μL/well) can bind Human CD155, Fc Tag (Cat. No. CD5-H5251) with a linear range of 8-128 ng/mL.

TIGIT: CD155 inhibitor screening

Serial dilutions of Human TIGIT Neutralizing antibody were added into Human CD155, Fc Tag (Cat. No. CD5-H5251): Biotinylated Human TIGIT, Fc,Avitag (Cat. No. TIT-H82F1) binding reactions. The half maximal inhibitory concentration (IC50) is 0.06065 μg/mL.

Figure 3. Serial dilutions of Human TIGIT Neutralizing antibody were added into Human CD155, Fc Tag (Cat. No. CD5-H5251): Biotinylated Human TIGIT, Fc, Avitag (Cat. No. TIT-H82F1) binding reactions. The half-maximal inhibitory concentration (IC50) is 0.06065 μg/mL.

BLI

Loaded Human TIGIT, Fc Tag (Cat. No. TIT-H5254) on Protein A Biosensor, can bind Human CD155, His Tag (Cat. No. CD5-H5223) with an affinity constant of 0.98 μM as determined in BLI assay (ForteBio Octet Red96e).

Figure 4. Loaded Human TIGIT, Fc Tag (Cat. No. TIT-H5254) on Protein A Biosensor, can bind Human CD155, His Tag (Cat. No. CD5-H5223) with an affinity constant of 0.98 μM as determined in BLI assay (ForteBio Octet Red96e).

SPR

Anti-Human TIGIT MAb (Mouse IgG1) captured on CM5 chip via Anti-Mouse antibodies surface, can bind Human TIGIT, His Tag (Cat. No. TIT-H52H3) with an affinity constant of 3.93 nM as determined in a SPR assay (Biacore T200).

Figure 5. Anti-Human TIGIT MAb (Mouse IgG1) captured on CM5 chip via Anti-Mouse antibodies surface, can bind Human TIGIT, His Tag (Cat. No. TIT-H52H3) with an affinity constant of 3.93 nM as determined in an SPR assay (Biacore T200).

FACS

FACS assay shows that Human TIGIT, His Tag (Cat. No. TIT-H52H3) can bind to 293T cell overexpressing human CD155. The concentration of TIGIT used is 0.3 μg/mL.

Figure 6. FACS assay shows that Human TIGIT, His Tag (Cat. No. TIT-H52H3) can bind to 293T cell overexpressing human CD155. The concentration of TIGIT used is 0.3 μg/mL.

Table 2. Product list.

Cat.
No.
Species Product Description Structure Purity Feature
TAT-K004 Human Anti TIGIT ELISA Kit      
TIT-C52H7 Canine Canine TIGIT Protein,
His Tag
TIT-H5253 Human Human TIGIT Protein,
Mouse IgG2a Fc Tag, low endotoxin
TIT-R5259 Rabbit Rabbit TIGIT Protein,
Fc Tag
TIT-R5258 Rat Rat TIGIT Protein,
Fc Tag
TIT-C5254 Cynomolgus / Rhesus macaque Cynomolgus / Rhesus macaque
TIGIT Protein, Fc Tag
TIT-H82E5 Human Biotinylated Human TIGIT Protein, Avitag™,
His Tag (recommended for biopanning)
TIT-C5223 Cynomolgus / Rhesus macaque Cynomolgus / Rhesus macaque TIGIT Protein,
His Tag (HPLC-verified)
TIT-H82F1 Human Biotinylated Human TIGIT Protein, Fc,Avitag™
TIT-M52E6 Mouse Mouse TIGIT Protein,
His Tag
TIT-M5257 Mouse Mouse TIGIT Protein,
Fc Tag
TIT-H52H3 Human Human TIGIT Protein,
His Tag
TIT-H5254 Human Human TIGIT Protein,
Fc Tag

 

About ACROBiosystems

ACROBiosystems is a leading manufacturer of recombinant proteins and other critical reagents to support the development of target therapeutics. The company employs an application-oriented development strategy, with a particular focus on product design, quality control, and solution-based support. Our products and services enable anyone in the field of drug development to have a more intuitive and streamlined process.

To respond to the coronavirus pandemic, ACROBiosystems has developed SARS-CoV-2 antigens specifically designed and optimized for serological test kits, including Spike-derived antigen S1, RBD, and Nucleocapsid protein. Proteins have been supplied to diagnostic companies in large quantities.


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Last updated: Sep 17, 2020 at 3:31 AM

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