Chemistry:Tremelimumab

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Short description: Monoclonal antibody
Tremelimumab
Tremelimumab 5GGV.png
Fab fragment of tremelimumab (blue) binding CTLA-4 (green). From PDB entry 5GGV.
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetCTLA-4
Clinical data
Trade namesImjudo
Other namestremelimumab-actl, ticilimumab, CP-675, CP-675,206
AHFS/Drugs.comMonograph
MedlinePlusa622078
License data
Pregnancy
category
Routes of
administration		Intravenous
Drug classAntineoplastic agent
ATC code
Legal status
Legal status
Identifiers
CAS Number
IUPHAR/BPS
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
FormulaC6500H9974N1726O2026S52
Molar mass146382.47 g·mol−1
 ☒N☑Y (what is this?)  (verify)

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).[6][7] 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).[7]

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).[7]

Tremelimumab was approved for medical use in the United States in October 2022,[6][8][9] and in the European Union in February 2023.[7]

Medical uses

Tremelimumab is indicated, in combination with durvalumab, for the treatment of adults with unresectable hepatocellular carcinoma.[6][10][7]

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.[7]

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.[11]

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.[12] 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.[12]

Unlike Ipilimumab (another fully human anti-CTLA-4 monoclonal antibody), which is an IgG1 isotype, tremelimumab is an IgG2 isotype.[13][14]

History

Previously in development by Pfizer,[15] it is in investigation by MedImmune, a wholly owned subsidiary of AstraZeneca.[16]

Clinical trials

Melanoma

Phase I and II clinical studies in metastatic melanoma showed some responses.[17] However, based on early interim analysis of phase III data, Pfizer designated tremelimumab as a failure and terminated the trial in April 2008.[15][18]

However, within a year, the survival curves showed separation of the treatment and control groups.[19]

Mesothelioma

Although it was designated in April 2015 as orphan drug status in mesothelioma,[20] 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.[21][22]

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.[23] 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.[24]

Society and culture

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.[25] The applicant for this medicinal product is AstraZeneca AB.[25] Tremelimumab was approved for medical use in the European Union in February 2023.[7][26]

Names

Tremelimumab is the international nonproprietary name (INN).[27]

References

  1. ↑ "Imjudo". 29 June 2023. https://www.tga.gov.au/resources/auspmd/imjudo. 
  2. ↑ "Imjudo (AstraZeneca Pty Ltd)". 28 July 2023. https://www.tga.gov.au/resources/prescription-medicines-registrations/imjudo-astrazeneca-pty-ltd. 
  3. ↑ "Notice: Multiple additions to the Prescription Drug List (PDL) [2023-10-26"]. 26 October 2023. https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/prescription-drug-list/notices-changes/multiple-additions-2023-10-26.html. 
  4. ↑ "Summary Basis of Decision (SBD) for Imjudo". 3 January 2024. https://dhpp.hpfb-dgpsa.ca/review-documents/resource/SBD1704300260963. 
  5. ↑ "Details for: Imjudo". 23 October 2023. https://dhpp.hpfb-dgpsa.ca/dhpp/resource/102967. 
  6. ↑ 6.0 6.1 6.2 6.3 "Imjudo- tremelimumab injection, solution". 10 November 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6690679c-be2f-4588-a2e4-89fff74dd6be. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 "Imjudo EPAR". 9 December 2022. https://www.ema.europa.eu/en/medicines/human/EPAR/imjudo.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  8. ↑ "Drug Approval Package: Imjudo". 4 November 2022. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761289Orig1s000TOC.cfm. 
  9. ↑ "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.
  10. ↑ "FDA approves tremelimumab in combination with durvalumab and platinum-". 10 November 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tremelimumab-combination-durvalumab-and-platinum-based-chemotherapy-metastatic-non. 
  11. ↑ "Tumor immunotherapy directed at PD-1". The New England Journal of Medicine 366 (26): 2517–9. June 2012. doi:10.1056/NEJMe1205943. PMID 22658126. 
  12. ↑ 12.0 12.1 "Tremelimumab". https://www.cancer.gov/publications/dictionaries/cancer-drug.  This article incorporates text from this source, which is in the public domain.
  13. ↑ "Gateways to clinical trials". Methods Find Exp Clin Pharmacol 30 (8): 643–72. October 2008. doi:10.1358/mf.2008.30.5.1236622. PMID 19088949. 
  14. ↑ Poust J (December 2008). "Targeting metastatic melanoma". Am J Health Syst Pharm 65 (24 Suppl 9): S9–S15. doi:10.2146/ajhp080461. PMID 19052265. 
  15. ↑ 15.0 15.1 "Pfizer Announces Discontinuation of Phase III Clinical Trial for Patients with Advanced Melanoma". Pfizer.com. 1 April 2008. http://www.pfizer.com/news/press-release/press-release-detail/pfizer_announces_discontinuation_of_phase_iii_clinical_trial_for_patients_with_advanced_melanoma. 
  16. ↑ Mechanism of Pathway: CTLA-4 Inhibition[yes|permanent dead link|dead link}}]
  17. ↑ "Biologic and immunomodulatory events after CTLA-4 blockade with ticilimumab in patients with advanced malignant melanoma". Cancer 106 (11): 2437–44. June 2006. doi:10.1002/cncr.21854. PMID 16615096. 
  18. ↑ "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. February 2013. doi:10.1200/JCO.2012.44.6112. PMID 23295794. 
  19. ↑ "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. May 2010. doi:10.1200/jco.2010.28.15_suppl.2609. 
  20. ↑ "FDA Grants AstraZeneca's Tremelimumab Orphan Drug Status for Mesothelioma". Mesothelioma Cancer Alliance. 17 April 2015. http://www.mesothelioma.com/news/2015/04/fda-grants-astrazenecas-tremelimumab-orphan-drug-status-for-mesothelioma.htm. 
  21. ↑ "Tremelimumab Fails Mesothelioma Drug Trial". FDA News Alert. 29 February 2016. http://www.fdanewsalert.com/astrazeneca-fails-mesothelioma-drug-trial/8517952/. 
  22. ↑ "AZ' tremelimumab fails in mesothelioma trial". PharmaTimes. 1 March 2016. http://www.pharmatimes.com/Article/16-03-01/AZ_tremelimumab_fails_in_mesothelioma_trial.aspx. 
  23. ↑ "AstraZeneca's immuno-oncology combo fails crucial Mystic trial in lung cancer". FierceBiotech. 27 July 2017. http://www.fiercebiotech.com/biotech/astrazeneca-hit-by-mystic-lung-cancer-pfs-failure. 
  24. ↑ "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.
  25. ↑ 25.0 25.1 "Imjudo: Pending EC decision". 15 December 2022. https://www.ema.europa.eu/en/medicines/human/summaries-opinion/imjudo.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  26. ↑ "Imjudo Product information". 23 February 2023. https://ec.europa.eu/health/documents/community-register/html/h1713.htm. 
  27. ↑ "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 59". WHO Drug Information 22 (1). 2008. 



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