Tremelimumab

Last updated

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
AHFS/Drugs.com Monograph
MedlinePlus a622078
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
 X mark.svgNYes check.svgY  (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). [7] [8] 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). [8]

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). [8]

Tremelimumab was approved for medical use in the United States in October 2022, [7] [9] [10] and in the European Union in February 2023. [8]

Medical uses

Tremelimumab is indicated, in combination with durvalumab, for the treatment of adults with unresectable hepatocellular carcinoma. [7] [11] [8]

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. [8]

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. [12]

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. [13] 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. [13]

Unlike Ipilimumab (another fully human anti-CTLA-4 monoclonal antibody), which is an IgG1 isotype, tremelimumab is an IgG2 isotype. [14] [15]

History

Previously in development by Pfizer, [16] it is in investigation by MedImmune, a wholly owned subsidiary of AstraZeneca. [17]

Clinical trials

Melanoma

Phase I and II clinical studies in metastatic melanoma showed some responses. [18] However, based on early interim analysis of phase III data, Pfizer designated tremelimumab as a failure and terminated the trial in April 2008. [16] [19]

However, within a year, the survival curves showed separation of the treatment and control groups. [20]

Mesothelioma

Although it was designated in April 2015 as orphan drug status in mesothelioma, [21] 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. [22] [23]

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. [24] 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. [25]

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. [26] The applicant for this medicinal product is AstraZeneca AB. [26] Tremelimumab was approved for medical use in the European Union in February 2023. [8] [27]

Names

Tremelimumab is the international nonproprietary name (INN). [28]

Related Research Articles

<span class="mw-page-title-main">AstraZeneca</span> British pharmaceutical company

AstraZeneca plc (AZ) is a British-Swedish multinational pharmaceutical and biotechnology company with its headquarters at the Cambridge Biomedical Campus in Cambridge, England. It has a portfolio of products for major diseases in areas including oncology, cardiovascular, gastrointestinal, infection, neuroscience, respiratory, and inflammation. It was involved in developing the Oxford–AstraZeneca COVID-19 vaccine.

<span class="mw-page-title-main">Pemetrexed</span> Chemical compound

Pemetrexed, sold under the brand name Alimta among others, is a chemotherapy medication for the treatment of pleural mesothelioma and non-small cell lung cancer (NSCLC).

<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology (immuno-oncology) and a growing subspecialty of oncology.

<span class="mw-page-title-main">Sorafenib</span> Chemical compound

Sorafenib, sold under the brand name Nexavar, is a kinase inhibitor drug approved for the treatment of primary kidney cancer, advanced primary liver cancer, FLT3-ITD positive AML and radioactive iodine resistant advanced thyroid carcinoma.

<span class="mw-page-title-main">Ipilimumab</span> Pharmaceutical drug

Ipilimumab, sold under the brand name Yervoy, is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

<span class="mw-page-title-main">Lenvatinib</span> Chemical compound

Lenvatinib, sold under the brand name Lenvima among others, is an anti-cancer medication for the treatment of certain kinds of thyroid cancer and for other cancers as well. It was developed by Eisai Co. and acts as a multiple kinase inhibitor against the VEGFR1, VEGFR2 and VEGFR3 kinases.

<span class="mw-page-title-main">Cabozantinib</span> Chemical compound

Cabozantinib, sold under the brand names Cometriq and Cabometyx among others, is an anti-cancer medication used to treat medullary thyroid cancer, renal cell carcinoma, and hepatocellular carcinoma. It is a small-molecule tyrosine-kinase inhibitor (TKI) of c-Met (HGFR) and VEGFR2, and also inhibits AXL, RET, and FLT3. It was discovered and developed by Exelixis Inc.

<span class="mw-page-title-main">Selumetinib</span> Chemical compound

Selumetinib (INN), sold under the brand name Koselugo, is a medication for the treatment of children, two years of age and older, with neurofibromatosis type I (NF-1), a genetic disorder of the nervous system causing tumors to grow on nerves. It is taken by mouth.

<span class="mw-page-title-main">Nivolumab</span> Anticancer medication

Nivolumab, sold under the brand name Opdivo, is an anti-cancer medication used to treat a number of types of cancer. This includes melanoma, lung cancer, malignant pleural mesothelioma, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, urothelial carcinoma, colon cancer, esophageal squamous cell carcinoma, liver cancer, gastric cancer, and esophageal or gastroesophageal junction cancer. It is administered intravenously.

<span class="mw-page-title-main">Pembrolizumab</span> Pharmaceutical drug used in cancer treatment

Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody, more specifically a PD-1 Inhibitor, used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast cancer. It is administered by slow intravenous injection.

Anifrolumab, sold under the brand name Saphnelo, is a monoclonal antibody used for the treatment of systemic lupus erythematosus. It binds to the type I interferon receptor, blocking the activity of type I interferons such as interferon-α and interferon-β.

<span class="mw-page-title-main">Binimetinib</span> Chemical compound

Binimetinib, sold under the brand name Mektovi, is an anti-cancer medication used to treat various cancers. Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway. Inappropriate activation of the pathway has been shown to occur in many cancers. In June 2018 it was approved by the FDA in combination with encorafenib for the treatment of patients with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma. In October 2023, it was approved by the FDA for treatment of NSCLC with a BRAF V600E mutation in combination with encorafenib. It was developed by Array Biopharma.

<span class="mw-page-title-main">Durvalumab</span> Pharmaceutical drug

Durvalumab, sold under the brand name Imfinzi, is an FDA-approved immunotherapy for cancer, developed by Medimmune/AstraZeneca. It is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks the interaction of programmed cell death ligand 1 (PD-L1) with the PD-1 (CD279).

<span class="mw-page-title-main">Atezolizumab</span> Monoclonal anti-PD-L1 antibody

Atezolizumab, sold under the brand name Tecentriq among others, is a monoclonal antibody medication used to treat urothelial carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma and alveolar soft part sarcoma, but discontinued for use in triple-negative breast cancer (TNBC). It is a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death-ligand 1 (PD-L1).

The immune-related response criteria (irRC) is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment, where the compound being evaluated is an immuno-oncology drug. Immuno-oncology, part of the broader field of cancer immunotherapy, involves agents which harness the body's own immune system to fight cancer. Traditionally, patient responses to new cancer treatments have been evaluated using two sets of criteria, the WHO criteria and the response evaluation criteria in solid tumors (RECIST). The immune-related response criteria, first published in 2009, arose out of observations that immuno-oncology drugs would fail in clinical trials that measured responses using the WHO or RECIST Criteria, because these criteria could not account for the time gap in many patients between initial treatment and the apparent action of the immune system to reduce the tumor burden.

<span class="mw-page-title-main">PD-1 and PD-L1 inhibitors</span> Class of anticancer drugs

PD-1 inhibitors and PD-L1 inhibitors are a group of checkpoint inhibitor anticancer drugs that block the activity of PD-1 and PDL1 immune checkpoint proteins present on the surface of cells. Immune checkpoint inhibitors are emerging as a front-line treatment for several types of cancer.

<span class="mw-page-title-main">Tislelizumab</span> Monoclonal antibody

Tislelizumab, sold under the brand name Tevimbra among others, is a humanized monoclonal antibody directed against programmed death receptor-1. It is being developed by BeiGene.

<span class="mw-page-title-main">Tucatinib</span> Chemical compound

Tucatinib, sold under the brand name Tukysa, is an anticancer medication used for the treatment of HER2-positive breast cancer. It is a small molecule inhibitor of HER2. It was developed by Array BioPharma and licensed to Cascadian Therapeutics.

Checkpoint inhibitor therapy is a form of cancer immunotherapy. The therapy targets immune checkpoints, key regulators of the immune system that when stimulated can dampen the immune response to an immunologic stimulus. Some cancers can protect themselves from attack by stimulating immune checkpoint targets. Checkpoint therapy can block inhibitory checkpoints, restoring immune system function. The first anti-cancer drug targeting an immune checkpoint was ipilimumab, a CTLA4 blocker approved in the United States in 2011.

<span class="mw-page-title-main">Trastuzumab deruxtecan</span> Medication

Trastuzumab deruxtecan, sold under the brand name Enhertu, is an antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab (Herceptin) covalently linked to the topoisomerase I inhibitor deruxtecan. It is licensed for the treatment of breast cancer or gastric or gastroesophageal adenocarcinoma. Trastuzumab binds to and blocks signaling through epidermal growth factor receptor 2 (HER2/neu) on cancers that rely on it for growth. Additionally, once bound to HER2 receptors, the antibody is internalized by the cell, carrying the bound deruxtecan along with it, where it interferes with the cell's ability to make DNA structural changes and replicate its DNA during cell division, leading to DNA damage when the cell attempts to replicate itself, destroying the cell.

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. Archived from the original on 11 September 2023. Retrieved 10 September 2023.
  3. "AusPAR: Imjudo". www.tga.gov.au.
  4. "Notice: Multiple additions to the Prescription Drug List (PDL) [2023-10-26]". Health Canada . 26 October 2023. Archived from the original on 3 January 2024. Retrieved 3 January 2024.
  5. "Summary Basis of Decision (SBD) for Imjudo". Health Canada . 3 January 2024. Archived from the original on 17 January 2024. Retrieved 17 January 2024.
  6. "Details for: Imjudo". Health Canada . 23 October 2023. Archived from the original on 17 January 2024. Retrieved 17 January 2024.
  7. 1 2 3 4 "Imjudo- tremelimumab injection, solution". DailyMed. 10 November 2022. Archived from the original on 18 November 2022. Retrieved 18 November 2022.
  8. 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.
  9. "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.
  10. "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.
  11. "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.
  12. 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.
  13. 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 .
  14. 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.
  15. Poust J (December 2008). "Targeting metastatic melanoma". Am J Health Syst Pharm. 65 (24 Suppl 9): S9–S15. doi:10.2146/ajhp080461. PMID   19052265.
  16. 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.
  17. Mechanism of Pathway: CTLA-4 Inhibition [ permanent dead link ]
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. McKee S (1 March 2016). "AZ' tremelimumab fails in mesothelioma trial". PharmaTimes. Archived from the original on 6 March 2016. Retrieved 6 March 2016.
  24. 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.
  25. "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.
  26. 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.
  27. "Imjudo Product information". Union Register of medicinal products. 23 February 2023. Archived from the original on 27 February 2023. Retrieved 2 March 2023.
  28. World Health Organization (2008). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 59". WHO Drug Information. 22 (1). hdl: 10665/74120 .