Tremelimumab

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Tremelimumab
Tremelimumab 5GGV.png
Fab fragment of tremelimumab (blue) binding CTLA-4 (green). From PDB entry 5GGV .
Monoclonal antibody
Type Whole antibody
Source Human
Target CTLA-4
Clinical data
Trade names Imjudo
Other namestremelimumab-actl, ticilimumab, CP-675, CP-675,206
License data
Pregnancy
category
Routes of
administration 		Intravenous
Drug class Antineoplastic agent
ATC code
Legal status
Legal status
Identifiers
CAS Number
IUPHAR/BPS
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
Formula C6500H9974N1726O2026S52
Molar mass 146382.47 g·mol−1
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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). [3] [4] 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). [4]

Contents

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). [4]

Tremelimumab was approved for medical use in the United States in October 2022, [3] [5] [6] and in the European Union in February 2023. [4]

Medical uses

Tremelimumab is indicated, in combination with durvalumab, for the treatment of adults with unresectable hepatocellular carcinoma. [3] [7] [4]

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. [4]

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. [8]

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. [9] 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. [9]

Unlike Ipilimumab (another fully human anti-CTLA-4 monoclonal antibody), which is an IgG1 isotype, tremelimumab is an IgG2 isotype. [10] [11]

History

Previously in development by Pfizer, [12] it is in investigation by MedImmune, a wholly owned subsidiary of AstraZeneca. [13]

Clinical trials

Melanoma

Phase I and II clinical studies in metastatic melanoma showed some responses. [14] However, based on early interim analysis of phase III data, Pfizer designated tremelimumab as a failure and terminated the trial in April 2008. [12] [15]

However, within a year, the survival curves showed separation of the treatment and control groups. [16]

Mesothelioma

Although it was designated in April 2015 as orphan drug status in mesothelioma, [17] 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. [18] [19]

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. [20] 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. [21]

Society and culture

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. [22] The applicant for this medicinal product is AstraZeneca AB. [22] Tremelimumab was approved for medical use in the European Union in February 2023. [4] [23]

Names

Tremelimumab is the international nonproprietary name (INN). [24]

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References

  1. ↑ "Imjudo". Therapeutic Goods Administration (TGA). 29 June 2023. Retrieved 10 September 2023.
  2. ↑ "Imjudo (AstraZeneca Pty Ltd)". Therapeutic Goods Administration (TGA). 28 July 2023. Retrieved 10 September 2023.
  3. 1 2 3 4 "Imjudo- tremelimumab injection, solution". DailyMed. 10 November 2022. Archived from the original on 18 November 2022. Retrieved 18 November 2022.
  4. 1 2 3 4 5 6 7 8 "Imjudo EPAR". European Medicines Agency (EMA). 9 December 2022. Archived from the original on 3 March 2023. Retrieved 2 March 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  5. ↑ "Drug Approval Package: Imjudo". U.S. Food and Drug Administration (FDA). 4 November 2022. Archived from the original on 3 March 2023. Retrieved 2 March 2023.
  6. ↑ "Imjudo (tremelimumab) in combination with Imfinzi approved in the US for patients with unresectable liver cancer". AstraZeneca (Press release). 26 October 2022. Archived from the original on 24 October 2022. Retrieved 26 October 2022.
  7. ↑ "FDA approves tremelimumab in combination with durvalumab and platinum-". U.S. Food and Drug Administration (FDA). 10 November 2022. Archived from the original on 20 December 2022. Retrieved 20 December 2022.
  8. ↑ Ribas A (June 2012). "Tumor immunotherapy directed at PD-1". The New England Journal of Medicine. 366 (26): 2517–9. doi:10.1056/NEJMe1205943. PMID   22658126.
  9. 1 2 "Tremelimumab". National Cancer Institute. Archived from the original on 10 August 2019. Retrieved 27 October 2022.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  10. ↑ Tomillero A, Moral MA (October 2008). "Gateways to clinical trials". Methods Find Exp Clin Pharmacol. 30 (8): 643–72. doi:10.1358/mf.2008.30.5.1236622. PMID   19088949.
  11. ↑ Poust J (December 2008). "Targeting metastatic melanoma". Am J Health Syst Pharm. 65 (24 Suppl 9): S9–S15. doi:10.2146/ajhp080461. PMID   19052265.
  12. 1 2 "Pfizer Announces Discontinuation of Phase III Clinical Trial for Patients with Advanced Melanoma". Pfizer.com. 1 April 2008. Archived from the original on 8 December 2015. Retrieved 5 December 2015.
  13. ↑ Mechanism of Pathway: CTLA-4 Inhibition [ permanent dead link ]
  14. ↑ Reuben JM, Lee BN, Li C, Gomez-Navarro J, Bozon VA, Parker CA, et al. (June 2006). "Biologic and immunomodulatory events after CTLA-4 blockade with ticilimumab in patients with advanced malignant melanoma". Cancer. 106 (11): 2437–44. doi: 10.1002/cncr.21854 . PMID   16615096.
  15. ↑ Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, et al. (February 2013). "Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma". Journal of Clinical Oncology. 31 (5): 616–22. doi: 10.1200/JCO.2012.44.6112 . PMC   4878048 . PMID   23295794.
  16. ↑ Marshall MA, Ribas A, Huang B (May 2010). "Evaluation of baseline serum C-reactive protein (CRP) and benefit from tremelimumab compared to chemotherapy in first-line melanoma". Journal of Clinical Oncology. 28 (15S): 2609. doi:10.1200/jco.2010.28.15_suppl.2609.
  17. ↑ Duff J (17 April 2015). "FDA Grants AstraZeneca's Tremelimumab Orphan Drug Status for Mesothelioma". Mesothelioma Cancer Alliance. Archived from the original on 31 July 2016.
  18. ↑ Krassenstein B (29 February 2016). "Tremelimumab Fails Mesothelioma Drug Trial". FDA News Alert. Archived from the original on 6 March 2016. Retrieved 6 March 2016.
  19. ↑ McKee S (1 March 2016). "AZ' tremelimumab fails in mesothelioma trial". PharmaTimes. Archived from the original on 6 March 2016. Retrieved 6 March 2016.
  20. ↑ Adams B (27 July 2017). "AstraZeneca's immuno-oncology combo fails crucial Mystic trial in lung cancer". FierceBiotech. Archived from the original on 17 May 2022. Retrieved 23 August 2017.
  21. ↑ "AstraZeneca reports initial results from the ongoing MYSTIC trial in Stage IV lung cancer". AstraZeneca (Press release). 27 July 2017. Archived from the original on 28 August 2021. Retrieved 23 August 2017.
  22. 1 2 "Imjudo: Pending EC decision". European Medicines Agency (EMA). 15 December 2022. Archived from the original on 16 December 2022. Retrieved 16 December 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  23. ↑ "Imjudo Product information". Union Register of medicinal products. 23 February 2023. Archived from the original on 27 February 2023. Retrieved 2 March 2023.
  24. ↑ World Health Organization (2008). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 59". WHO Drug Information. 22 (1). hdl: 10665/74120 .
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