Tremelimumab

Overview

Tremelimumab, sold under the brand name Imjudo, is a fully human monoclonal antibody used for the treatment of hepatocellular carcinoma (a type of liver cancer). Tremelimumab is designed to attach to and block CTLA-4, a protein that controls the activity of T cells, which are part of the immune system (the body’s natural defenses).[1][2] WP

The most common side effects when used in combination with durvalumab include rash, pruritus (itching), diarrhea, abdominal (belly) pain, increased levels of liver enzymes, fever, hypothyroidism (an underactive thyroid gland), cough, peripheral edema (swelling especially of the ankles and feet) and increased level of lipase (an enzyme that helps digest fat, mainly made in the pancreas).[2] WP

Tremelimumab was approved for medical use in the United States in October 2022, and in the European Union in February 2023.[1–4] WP

Drug class

Antineoplastic WP

From the Wikipedia article's infobox.

Uses, dosage and effects

Medical uses

Tremelimumab is indicated, in combination with durvalumab, for the treatment of adults with unresectable hepatocellular carcinoma.[1][2][5] WP

Tremelimumab in combination with durvalumab and platinum-based chemotherapy is indicated for the first-line treatment of adults with metastatic non-small cell lung cancer with no sensitizing epidermal growth factor receptor mutations or anaplastic lymphoma kinase positive mutations.[2] WP

Pharmacology

Mechanism of action

Tremelimumab aims to stimulate an immune system attack on tumors. Cytotoxic T lymphocytes (CTLs) can recognize and destroy cancer cells. However, there is also an inhibitory mechanism (immune checkpoint) that interrupts this destruction. Tremelimumab turns off this inhibitory mechanism and allows CTLs to continue to destroy the cancer cells.[6] WP

Like ipilimumab, tremelimumab is antibody that binds to the protein CTLA-4, which is expressed on the surface of activated T lymphocytes and inhibits the killing of cancer cells. Tremelimumab blocks the binding of the antigen-presenting cell ligands B7.1 and B7.2 to CTLA-4, resulting in inhibition of B7-CTLA-4-mediated downregulation of T-cell activation; subsequently, B7.1 or B7.2 may interact with another T-cell surface receptor protein, CD28, resulting in a B7-CD28-mediated T-cell activation unopposed by B7-CTLA-4-mediated inhibition.[7] WP

Unlike Ipilimumab (another fully human anti-CTLA-4 monoclonal antibody), which is an IgG1 isotype, tremelimumab is an IgG2 isotype.[8][9] WP

History

History

Previously in development by Pfizer, it is in investigation by MedImmune, a wholly owned subsidiary of AstraZeneca.[10][11] WP

Melanoma

Phase I and II clinical studies in metastatic melanoma showed some responses. However, based on early interim analysis of phase III data, Pfizer designated tremelimumab as a failure and terminated the trial in April 2008.[10][12][13] WP

However, within a year, the survival curves showed separation of the treatment and control groups.[14] WP

Mesothelioma

Although it was designated in April 2015 as orphan drug status in mesothelioma tremelimumab failed to improve lifespan in the phase IIb DETERMINE trial, which assessed the drug as a second or third-line treatment for unresectable malignant mesothelioma.[15][16] WP

Non-small cell lung cancer

In a phase III trial, AstraZeneca paired tremelimumab with a PD-L1 inhibitor, durvalumab, for the first-line treatment of non-small cell lung cancer. The trial was conducted across 17 countries, and in July 2017, AstraZeneca announced that it had failed to meet its primary endpoint of progression-free survival.[17][18] WP

Legal status

Legal status

On 15 December 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Imjudo, intended for the treatment of hepatocellular carcinoma. The applicant for this medicinal product is AstraZeneca AB. Tremelimumab was approved for medical use in the European Union in February 2023.[2][19][20] WP

Names

Tremelimumab is the international nonproprietary name (INN).[21] WP

Chemistry

Harm reduction information

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User reports

Pop culture

No references added yet.

Sources

1. Journal / agency Imjudo- tremelimumab injection, solution. 10 November 2022
2. Journal / agency Imjudo EPAR. 9 December 2022
3. Journal / agency Drug Approval Package: Imjudo. 4 November 2022
4. Other Imjudo (tremelimumab) in combination with Imfinzi approved in the US for patients with unresectable liver cancer. 26 October 2022
5. Journal / agency FDA approves tremelimumab in combination with durvalumab and platinum-. 10 November 2022
6. Journal / agency Ribas A. Tumor immunotherapy directed at PD-1. The New England Journal of Medicine. June 2012. doi:10.1056/NEJMe1205943 · PMID 22658126
7. Other Tremelimumab
8. Journal / agency Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. October 2008. doi:10.1358/mf.2008.30.5.1236622 · PMID 19088949
9. Journal / agency Poust J. Targeting metastatic melanoma. Am J Health Syst Pharm. December 2008. doi:10.2146/ajhp080461 · PMID 19052265
10. Other Pfizer Announces Discontinuation of Phase III Clinical Trial for Patients with Advanced Melanoma. 1 April 2008
11. Other Mechanism of Pathway: CTLA-4 Inhibition
12. Journal / agency Reuben JM, Lee BN, Li C, Gomez-Navarro J, Bozon VA, Parker CA, Hernandez IM, Gutierrez C, Lopez-Berestein G, Camacho LH. Biologic and immunomodulatory events after CTLA-4 blockade with ticilimumab in patients with advanced malignant melanoma. Cancer. June 2006. doi:10.1002/cncr.21854 · PMID 16615096
13. Journal / agency Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, Garbe C, Gogas H, Schachter J, Linette G, Lorigan P, Kendra KL, Maio M, Trefzer U, Smylie M, McArthur GA, Dreno B, Nathan PD, Mackiewicz J, Kirkwood JM, Gomez-Navarro J, Huang B, Pavlov D, Hauschild A. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. Journal of Clinical Oncology. February 2013. doi:10.1200/JCO.2012.44.6112 · PMID 23295794 · PMC4878048
14. Journal / agency Marshall MA, Ribas A, Huang B. Evaluation of baseline serum C-reactive protein (CRP) and benefit from tremelimumab compared to chemotherapy in first-line melanoma. Journal of Clinical Oncology. May 2010. doi:10.1200/jco.2010.28.15_suppl.2609
15. Other Krassenstein B. Tremelimumab Fails Mesothelioma Drug Trial. 29 February 2016
16. Other McKee S. AZ' tremelimumab fails in mesothelioma trial. 1 March 2016
17. Other Adams B. AstraZeneca's immuno-oncology combo fails crucial Mystic trial in lung cancer. 27 July 2017
18. Other AstraZeneca reports initial results from the ongoing MYSTIC trial in Stage IV lung cancer. 27 July 2017
19. Journal / agency Imjudo: Pending EC decision. 15 December 2022
20. Other Imjudo Product information. 23 February 2023
21. Journal / agency World Health Organization. International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 59. WHO Drug Information. 2008

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