Tiragolumab
| Monoclonal antibody | |
|---|---|
| Type | ? |
| Clinical data | |
| Synonyms | RG6058, MTIG7192A |
| Routes of administration | Intravenous |
| Drug class | Immune checkpoint inhibitor |
| Identifiers | |
| CAS Number | |
| UNII | |
| KEGG | |
| ChEBI | |
| E number | {{#property:P628}} |
| ECHA InfoCard | {{#property:P2566}} |
| Chemical and physical data | |
| Formula | C6620H10206N1742O2074S40 |
| Molar mass | 148664.99 g·mol−1 |
Tiragolumab (development names RG6058 and MTIG7192A) is a humanized monoclonal antibody that functions as an immune checkpoint inhibitor by targeting the T-cell immunoreceptor with Ig and ITIM domains (TIGIT) pathway.[1][2] Developed by Genentech and Roche, the drug is designed to enhance anti-tumor immune responses when used in combination with other immunotherapy agents, particularly atezolizumab (Tecentriq).[1]
In January 2021, tiragolumab received breakthrough therapy designation from the U.S. Food and Drug Administration (FDA) for use in combination with atezolizumab in the treatment of patients with PD-L1-high metastatic non-small-cell lung cancer (NSCLC) who do not harbor EGFR mutations or ALK rearrangements.[3]
Mechanism of action
Tiragolumab is a fully human IgG1/kappa monoclonal antibody that specifically binds to TIGIT, preventing its interaction with its primary ligand, the poliovirus receptor (PVR, also known as CD155).[4] TIGIT is an inhibitory immune checkpoint receptor primarily expressed on T cells and natural killer (NK) cells that normally suppresses anti-tumor immune responses through multiple mechanisms.[5]
The therapeutic mechanism of tiragolumab involves blocking the TIGIT-PVR interaction, which normally leads to T cell inhibition and immune suppression in the tumor microenvironment.[6] By preventing this inhibitory signaling, tiragolumab aims to restore and enhance anti-tumor T cell responses. Additionally, preclinical studies have demonstrated that tiragolumab surrogate antibodies can activate tumor-associated macrophages, monocytes, and dendritic cells through Fcγ receptors, leading to the transformation of exhausted CD8+ T cells into a more memory-like state with enhanced anti-tumor activity.[5]
Clinical development
Phase I studies
The initial clinical evaluation of tiragolumab was conducted through a Phase 1a/1b dose-escalation and dose-expansion study (GO30103, NCT02794571), which investigated both single-agent tiragolumab and its combination with atezolizumab in patients with advanced solid tumors.[7]
The study demonstrated that tiragolumab in combination with atezolizumab was tolerable and showed preliminary antitumor activity across various solid tumor types.[4][8][9][10]
Pharmacodynamic studies from the Phase I trial revealed that peripheral TIGIT receptors on CD8+ T cells were completely occupied for sustained periods at tiragolumab doses of at least 30 mg administered every three weeks, with clinical activity observed at doses ranging from 400 mg to 600 mg every three weeks.[11]
Phase II CITYSCAPE trial
The pivotal Phase II CITYSCAPE trial (NCT03563716) was a randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of tiragolumab in combination with atezolizumab as first-line therapy in patients with PD-L1-positive advanced NSCLC.[12][13] This study represented the first randomized investigation in the anti-TIGIT therapeutic field and enrolled a total of 135 patients.[14][15]
The CITYSCAPE trial provided the first evidence of enhanced anti-tumor activity when targeting both TIGIT and PD-L1 immune inhibitory receptors simultaneously, potentially amplifying the immune response against tumors.[16] The encouraging efficacy and safety results from this trial formed the basis for the FDA's breakthrough therapy designation.[1][17]
Other clinical investigations
Tiragolumab has also been investigated in other malignancies, including small-cell lung cancer (SCLC) through the SKYSCRAPER-02 trial and esophageal cancer.[11][18]
Additionally, dedicated studies have been conducted to evaluate the drug's safety and efficacy in Japanese patients with advanced or metastatic solid tumors.[19]
Regulatory status
In January 2021, the FDA granted breakthrough therapy designation to tiragolumab in combination with atezolizumab for the treatment of patients with metastatic NSCLC whose tumors are PD-L1-high and do not harbor EGFR mutations or ALK rearrangements.[3] This designation was based on the results from the Phase II CITYSCAPE study, which demonstrated improved clinical outcomes in this patient population.[20][21]
See also
References
- ↑ 1.0 1.1 1.2 "Roche's novel anti-TIGIT tiragolumab granted FDA Breakthrough Therapy Designation in combination with Tecentriq for PD-L1-high non-small cell lung cancer". www.roche.com. Archived from the original on 3 May 2025. Retrieved 2025-07-21. Unknown parameter
|url-status=ignored (help) - ↑ "Tiragolumab (anti-TIGIT) Immunology & Inflammation related inhibitor | Read Reviews & Product Use Citations". www.selleckchem.com. Archived from the original on 22 December 2024. Retrieved 2025-07-21. Unknown parameter
|url-status=ignored (help) - ↑ 3.0 3.1 Rosa K (2021-01-05). "FDA Grants Breakthrough Therapy Designation to Tiragolumab Plus Atezolizumab for PD-L1–High NSCLC". OncLive. Archived from the original on 3 May 2025. Retrieved 2025-07-21. Unknown parameter
|url-status=ignored (help) - ↑ 4.0 4.1 Wainberg Z, Matos I, Delord J, Cassier P, Gil-Martin M, Kim T, Lorusso P, Bahleda R, Italiano A, Mendus D, Hoang T, Xue C, Wen X, Carvalho O, Pham T, Patil N, Meng R, Bendell J, Cervantes A, Cho B (2021). "Phase Ib study of the anti-TIGIT antibody tiragolumab in combination with atezolizumab in patients with metastatic esophageal cancer". Annals of Oncology. 32: S227–S228. doi:10.1016/j.annonc.2021.06.012. Retrieved 2025-01-21.
- ↑ 5.0 5.1 Guan X, Hu R, Choi Y, Srivats S, Nabet BY, Silva J, McGinnis L, Hendricks R, Nutsch K, Banta KL, Duong E, Dunkle A, Chang PS, Han CJ, Mittman S (2024-03-01). "Anti-TIGIT antibody improves PD-L1 blockade through myeloid and Treg cells". Nature. 627 (8004): 646–655. doi:10.1038/s41586-024-07121-9. ISSN 1476-4687. PMC 11139643 Check
|pmc=value (help). PMID 38418879 Check|pmid=value (help). - ↑ Rui S, Kong X, Liu J, Wang L, Wang X, Zou X, Zheng X, Ye F, Xu H, Li Z, Luo H (2022). "The landscape of TIGIT target and clinical application in diseases". MedComm – Oncology. 1 (2). doi:10.1002/mog2.18. ISSN 2769-6448. Unknown parameter
|article-number=ignored (help) - ↑ Kim TW, Bedard PL, Lorusso P, Gordon MS, Bendell J, Oh DY, Ahn MJ, Garralda E, d'Angelo SP, Desai J, Hodi FS, Wainberg Z, Delord JP, Cassier PA, Cervantes A, Gil-Martin M, Wu B, Patil NS, Jin Y, Hoang T, Mendus D, Wen X, Meng R, Cho BC (2023-09-28). "Anti-TIGIT Antibody Tiragolumab Alone or With Atezolizumab in Patients With Advanced Solid Tumors: A Phase 1a/1b Nonrandomized Controlled Trial". JAMA Oncology. 9 (11): 1574–1582. doi:10.1001/jamaoncol.2023.3867. PMC 10540058 Check
|pmc=value (help). PMID 37768658 Check|pmid=value (help). - ↑ Genentech, Inc. (2024-12-04). A Phase Ia/Ib Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics of Tiragolumab as a Single Agent and in Combination With Atezolizumab and/or Other Anti-Cancer Therapies in Patients With Locally Advanced or Metastatic Tumors (Report). clinicaltrials.gov. Archived from the original on 25 March 2025. Retrieved 21 July 2025. Unknown parameter
|url-status=ignored (help) - ↑ Garralda E, Oh DY, Italiano A, Bedard PL, Delord JP, Calvo E, LoRusso P, Wainberg Z, Cervantes A, Rodriguez-Vida A, Shemesh CS, Sane R, Mendus D, Ding H, Hendricks R (2024-05-01). "Pharmacokinetics (PK) of Tiragolumab in First-in-Human Study in Patients with Mixed Solid Tumors (GO30103)". Journal of Clinical Pharmacology. 64 (5): 544–554. doi:10.1002/jcph.2397. hdl:10230/68333. ISSN 1552-4604. PMID 38105505 Check
|pmid=value (help). - ↑ Finn RS, Ryoo BY, Hsu CH, Li D, Burgoyne AM, Cotter C, Badhrinarayanan S, Wang Y, Yin A, Edubilli TR, Mahrus S, Secrest MH, Shemesh CS, Yu N, Hack SP (2025-02-01). "Tiragolumab in combination with atezolizumab and bevacizumab in patients with unresectable, locally advanced or metastatic hepatocellular carcinoma (MORPHEUS-Liver): a randomised, open-label, phase 1b–2, study". The Lancet. Oncology. 26 (2): 214–226. doi:10.1016/S1470-2045(24)00679-X. ISSN 1470-2045. PMID 39855251 Check
|pmid=value (help). - ↑ 11.0 11.1 Brazel D, Ou SH, Nagasaka M (2023). "Tiragolumab (Anti-TIGIT) in SCLC: Skyscraper-02, a Towering Inferno". Lung Cancer: Targets and Therapy. Auckland, N.Z. 14: 1–9. doi:10.2147/LCTT.S379389. ISSN 1179-2728. PMC 9831070 Check
|pmc=value (help). PMID 36636263 Check|pmid=value (help). - ↑ "TIGIT Inhibitor Drug Clinical Trials Report 2022". BioSpace. 2022-05-20. Retrieved 2025-01-21.
- ↑ Genentech, Inc. (2025-04-11). A Phase II, Randomized, Blinded, Placebo-Controlled Study of Tiragolumab, An Anti-TIGIT Antibody, In Combination With Atezolizumab In Chemotherapy-Naïve Patients With Locally Advanced Or Metastatic Non-Small Cell Lung Cancer (Report). clinicaltrials.gov. Archived from the original on 12 March 2025. Retrieved 21 July 2025. Unknown parameter
|url-status=ignored (help) - ↑ Niu J, Radhi S (2024). "Targeting TIGIT in lung cancer: will it stick to the wall?". AME Clinical Trials Review. 2: 40. doi:10.21037/actr-24-24. Archived from the original on 29 April 2025. Retrieved 2025-01-21. Unknown parameter
|url-status=ignored (help) - ↑ Cho BC, Abreu DR, Hussein M, Cobo M, Patel AJ, Secen N, Lee KH, Massuti B, Hiret S, Yang JC, Barlesi F, Lee DH, Ares LP, Hsieh RW, Patil NS (2022-06-01). "Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): primary and follow-up analyses of a randomised, double-blind, phase 2 study". The Lancet. Oncology. 23 (6): 781–792. doi:10.1016/S1470-2045(22)00226-1. ISSN 1470-2045. PMID 35576957 Check
|pmid=value (help). - ↑ "FDA Grants Breakthrough Therapy to First Anti-TIGIT Therapy in NSCLC With High PD-L1". Targeted Oncology. 2021-01-05. Archived from the original on 19 April 2025. Retrieved 2025-01-21. Unknown parameter
|url-status=ignored (help) - ↑ Cho BC, Abreu DR, Hussein M, Cobo M, Patel AJ, Secen N, Lee KH, Massuti B, Hiret S, Yang JC, Barlesi F, Lee DH, Ares LP, Hsieh RW, Patil NS (2022-06-01). "Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): primary and follow-up analyses of a randomised, double-blind, phase 2 study". The Lancet. Oncology. 23 (6): 781–792. doi:10.1016/S1470-2045(22)00226-1. ISSN 1474-5488. PMID 35576957 Check
|pmid=value (help). - ↑ Rudin CM, Liu SV, Soo RA, Lu S, Hong MH, Lee JS, Bryl M, Dumoulin DW, Rittmeyer A, Chiu CH, Ozyilkan O, Johnson M, Navarro A, Novello S, Ozawa Y (2024-01-20). "SKYSCRAPER-02: Tiragolumab in Combination With Atezolizumab Plus Chemotherapy in Untreated Extensive-Stage Small-Cell Lung Cancer". Journal of Clinical Oncology. 42 (3): 324–335. doi:10.1200/JCO.23.01363. ISSN 1527-7755. PMC 10824371 Check
|pmc=value (help). PMID 37976444 Check|pmid=value (help). - ↑ Yamamoto N, Koyama T, Sato J, Yoshida T, Sudo K, Iwasa S, Kondo S, Yonemori K, Kawasaki A, Satake K, Shibata S, Shimizu T (2024-07-01). "Phase I study of the anti-TIGIT antibody tiragolumab in combination with atezolizumab in Japanese patients with advanced or metastatic solid tumors". Cancer Chemotherapy and Pharmacology. 94 (1): 109–115. doi:10.1007/s00280-023-04627-3. ISSN 1432-0843. PMC 11258096 Check
|pmc=value (help). PMID 38206370 Check|pmid=value (help). - ↑ "Genentech's Novel Anti-TIGIT Tiragolumab Granted FDA Breakthrough Therapy Designation in Combination With Tecentriq for PD-L1-High Non-Small Cell Lung Cancer". BioSpace. 2021-01-05. Retrieved 2025-01-21.
- ↑ "Genentech's Novel Anti-TIGIT Tiragolumab Granted FDA Breakthrough Therapy Designation in Combination With Tecentriq for PD-L1-High Non-Small Cell Lung Cancer". Genentech: Press Releases. 4 January 2021. Archived from the original on 20 June 2025. Retrieved 2025-07-21. Unknown parameter
|url-status=ignored (help)
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