Advances in tumor immunotherapy research targeting TIGIT

preface

Over the past decade, the discovery of T-cell immune checkpoints and the development of monoclonal antibodies that inhibit checkpoints have dramatically altered the outcome of

Currently, TIGIT is considered one of the most promising and promising targets, with multiple pieces of evidence supporting TIGIT's key role

TIGIT function axes and ligands

TIGIT (also known as WUCAM, Vstm3, VSIG9) is a receptor of the Ig superfamily that plays a key role

TIGIT is expressed

TIGIT binds two ligands, CD155 and CD112, to express

TIGIT binds weakly to CD112, and CD112R binds CD112 with a higher affinity than CD226

TIGIT structure and signal path

TIGIT consists of an extracellular immunoglobulin (Ig) variable domain, a type 1 transmembrane domain, and an intracellular domain with two inhibitory motifs that are conserved in mice and humans: the immune receptor tyrosine-based inhibitory motif (ITIM) and the Ig-tail tyrosine-like (ITT) motif

In mice, phosphorylation of ITIM (Y227) or ITT-like sequence residues (Y233) triggers TIGIT inhibition signals

TIGIT's mechanism of action

TIGIT potentially inhibits innate and adaptive immunity

Second, TIGIT directly exhibits an intrinsic inhibitory effect

Third, multiple pieces of evidence suggest that TIGIT hinders CD155-mediated CD226 activation

Fourth, the equilibrium of TIGIT/CD226 expression regulates the effector function

Fifth, TIGIT acts on Tregs, enhancing immunosuppressive function and stability

Clinical advances in TIGIT-targeted drugs

Targeting the TIGIT-PVR pathway is becoming increasingly important, and some biotech/pharmaceutical companies are working on developing antibodies or di-antibodies that are anti-TIGIT

Looking at the world, developers have no shortage of roche, Bristol-Myers Squibb, Merck and other head big pharmaceutical companies

Domestic pharmaceutical companies are not lagging behind in the progress of TIGIT, and BeiGene, Innovent Biologics, Junshi Biological, BIT, Henlin Fuhong, Kangfang Biologics, etc.

Considerations during development

Factors such as the source of the antibody backbone (mouse, chimeric, humanized, or whole human), the IgG backbone of the antibody, the FcγR binding status and dose, play a key role
in the development and eventual clinical success of the antibody.

source

Sources of antibodies for therapeutic applications can significantly influence the clinical success
of molecules.
So far, all approved immune checkpoint blockers have been either humanized or fully human, and most anti-TIGIT antibodies in clinical development are fully human
.

FcγR binding state

Almost all commercially developed immune checkpoint blocking antibodies have an IgG backbone
.
IgG-based antibodies are known to interact with FcγR on innate effector immune cells through their Fc regions and induce antibody-dependent cytotoxicity (ADCC)
in target cells.
ADCC is the most common factor considered in the development of therapeutic antibodies, but its effect on immune checkpoint blocker activity is not fully understood
.

In clinical development, the FcγR binding region of anti-TIGIT antibodies is active in some molecules and inactivated in others
.
According to publicly available information, tiragolumab, ociperlimab, vibostolimab, EOS-448, etigilimab and AGEN-1307 have an active FcγR binding region, while domvanalimab and BMS-986207 have an inactive FcγR binding region
.
Whether the presence or absence of FcγR binding regions in antibodies will have an impact on the clinical efficacy of anti-TIGIT antibodies remains to be seen
.

dosage

Various factors, including affinity, pharmacodynamic factors, and pharmacokinetic factors, all affect the maximum tolerated dose and the dose at which the drug is expected to produce the greatest effect
.
The results of phase I studies in multiple clinical programs showed that anti-TIGIT antibodies were well tolerated
.

Studies use antibodies in different dose ranges, administered every two weeks (Q2W) or every three weeks (Q3W
).
During clinical development, no dose-limiting toxicity was recorded in either monotherapy with anti-TIGIT antibodies or in combination with anti-PD-1 antibodies, suggesting that molecules targeting this target have a broad therapeutic index
.
The clinical activity observed after monotherapy with anti-TIGIT antibodies was low or even zero, indicating the need for combination therapy
with anti-PD-1/PD-L1 or other drugs.

security

When used as monotherapy and in combination with PD-1/PD-L1 blockers, anti-TIGIT antibodies were generally found to be well tolerated
.
More than 10% of patients reported the most common adverse events, including fatigue and pruritus, both of which were grade
1.
Two grade 2 events, namely anemia and diarrhea
, were reported in two patients receiving vibostolimab monotherapy.
No adverse events
of grade 3 or above were reported with anti-TIGIT antibody monotherapy.

Challenges and outlook

TIGIT is a promising target for tumor immunotherapy, especially in combination with PD-1 blockers
.
However, as CLINICAL TRIALS FOR CANCER PATIENTS BASED ON TIGIT PROGRESS, WE NEED TO ADDRESS MANY KEY ISSUES AND CHALLENGES
.
First of all, what is the mechanism of action of TIGIT blockers on cancer patients? Are these effects primarily mediated by their direct activity in CD8+ T cells, Tregs, or both? Can TIGIT block the reprogramming of APCs in TME to increase the startup or activation of T cells? Will these effects vary depending on the stage of the disease? Can TIGIT blockers mediate NK cell-mediated responsiveness to MHCI-like defective tumors in vivo, and does this provide an opportunity for clinical benefit for patients with PD-1 refractory cancer? And, apart from the PD-1/TIGIT dual blocker, do CD112R or CD96 blockers have any potential synergistic effects, as shown in mouse tumor models and in vitro studies? In this regard, we must bear in mind that the role of CD96 as an IR remains controversial
.
In addition, evidence that CD112R blockade can potentially enhance autologous human tumor antigen-specific CD8+ T cells remains missing
.

In addition, CD226 plays an important regulatory role
in PD-1/TIGIT dual blocking.
Downregulation of CD8+ T cells and NK cells in TME may be a major obstacle
to the success of the PD-1/TIGIT double blockade.
Therefore, it is necessary to design new strategies to increase the expression and signal transmission of CD226 to prevent its downregulation
in TME.
Notably, an ongoing clinical trial is testing an anti-CD226 agonist (NCT04099277) in a variety of cancers
.
However, due to the role of CD226 in mediating platelet adhesion and activation, potential hematologic adverse events require careful monitoring
.
Finally, clinical trials using different engineered Fc antiTIGIT monoclonal antibodies may help determine the role
of FcγR synergy in TIGIT blockade.

In short, TIGIT has entered clinical trials as a target for immunotherapy only 10 years after its discovery
.
With the deepening of TIGIT-mediated immune response regulation research, it will help to optimize the combination strategy design of TIGIT blockers for cancer patients, and will also help develop TIGIT-targeted therapies to treat other chronic diseases
expressing this protein.

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