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Tiragolumab is a fully human IgG1κ monoclonal antibody that binds TIGIT (T-cell immunoreceptor with Ig and ITIM domains)—an inhibitory immune checkpoint expressed on CD8+ T cells, NK cells, and Tregs. Its core intent is to release TIGIT-mediated suppression and enhance anti-tumor immunity, most commonly in combination with PD-L1 blockade (atezolizumab/Tecentriq).

Regulatory status: investigational (not FDA/EMA-approved). Tiragolumab previously received FDA Breakthrough Therapy Designation for PD-L1-high metastatic NSCLC in combination with atezolizumab, based on early phase randomized data.

2) Target biology: why TIGIT matters (and why it’s tricky)

TIGIT competes with the activating receptor CD226 (DNAM-1) for binding to CD155 (PVR) and CD112, and also delivers direct inhibitory signaling via its cytoplasmic motifs. Net effect: reduced T-cell and NK cytotoxic function, and often a more suppressive tumor microenvironment.

The therapeutic challenge is that TIGIT biology is cell-context dependent:

• On effector T cells/NK cells, blockade can restore killing.

• On Tregs, TIGIT is often enriched; Fc-active antibodies may also alter Treg/NK dynamics via effector functions.

3) Molecular mechanism of action

3.1 Receptor pharmacodynamics

• Tiragolumab blocks TIGIT’s interaction with CD155 and CD112, reducing inhibitory signaling and promoting effector immune activity.

3.2 Systems-level “intended biology”

4) Pharmacokinetics and dosing (program-level)

As an IgG1 monoclonal antibody, tiragolumab follows typical mAb PK principles (FcRn recycling, slow clearance, distribution largely in vascular/interstitial spaces). In pivotal programs it was dosed on a multi-week schedule alongside atezolizumab ± chemotherapy (regimens varied by trial).

5) Clinical evidence (key trials and what they showed)

5.1 CITYSCAPE (Phase 2, first-line NSCLC): the early signal

In CITYSCAPE, tiragolumab + atezolizumab showed a clinically meaningful improvement in objective response rate and progression-free survival versus placebo + atezolizumab as first-line treatment in metastatic NSCLC, with signals strongest in PD-L1–high (TPS ≥50%) patients—this dataset underpinned Breakthrough Therapy Designation.

5.2 SKYSCRAPER-01 (Phase 3, PD-L1–high NSCLC): did not confirm benefit

In the Phase 3 confirmatory setting, SKYSCRAPER-01 did not meet its primary endpoints of overall survival and investigator-assessed PFS for tiragolumab + atezolizumab vs atezolizumab alone in previously untreated PD-L1–high advanced NSCLC (final analyses presented publicly).

5.3 SKYSCRAPER-02 (Phase 3, ES-SCLC): negative

In untreated extensive-stage small-cell lung cancer, adding tiragolumab to atezolizumab + carboplatin/etoposide did not provide additional benefit over control for OS/PFS; safety was generally consistent with expectations.

5.4 SKYSCRAPER-06 (Phase II/III, non-squamous NSCLC vs Keytruda regimen): halted for reduced efficacy

Roche reported SKYSCRAPER-06 (tiragolumab + atezolizumab + chemo vs pembrolizumab + chemo) missed PFS and OS and showed reduced efficacy vs comparator, leading Roche to halt the trial.

5.5 Beyond lung cancer: exploratory programs

Tiragolumab has been studied in other tumor types (e.g., PD-L1+ recurrent cervical cancer in a randomized phase II design), reflecting broad interest in TIGIT biology, but lung cancer was the most visible confirmatory path.

6) Safety and tolerability (most defensible points)

Across large combination trials, the safety profile is broadly consistent with checkpoint therapy + chemotherapypatterns, with:

• immune-mediated AEs (checkpoint class) and

• chemo-related toxicities when combined,
  plus trial-specific signals such as injection-site reactions reported in some combinations (where applicable). For SKYSCRAPER-06, Roche reported safety consistent with prior studies despite stopping for efficacy.

(For any program write-up, it’s best to ground AE language in the actual paper/CSR for the exact regimen and population.)

7) Why the Phase 2 signal didn’t translate (scientific synthesis)

The best-supported, non-speculative interpretation from the field and recent reviews is:

1. TIGIT biology is redundant and context-specific.
   Multiple inhibitory axes (PD-1/PD-L1, LAG-3, TIM-3, etc.) and variable ligand landscapes can dilute the incremental benefit of TIGIT blockade in Phase 3 populations.

2. Fc biology and cell-type expression complicate net effect.
   TIGIT is expressed on both effector and regulatory compartments; Fc-active antibodies can have competing effects depending on tumor context and immune composition.

3. Phase 2 enrichment effects may not hold at scale.
   CITYSCAPE’s encouraging PD-L1-high subgroup signals did not reproduce in confirmatory NSCLC trials.

8) Bottom line

Tiragolumab is a leading anti-TIGIT antibody that showed promising Phase 2 activity with atezolizumab in NSCLC (CITYSCAPE) and earned FDA Breakthrough Therapy Designation, but multiple later-stage studies in lung cancer—including SKYSCRAPER-01, -02, and -06—failed to demonstrate confirmatory benefit, with SKYSCRAPER-06 halted for reduced efficacy versus a pembrolizumab-based standard.