View source for Tremelimumab

{{Short description|Monoclonal antibody}}
{{Use dmy dates|date=January 2024}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 470612724
| type = mab
| image = Tremelimumab 5GGV.png
| width = 
| alt = 
| caption = [[Fragment antigen-binding|Fab fragment]] of tremelimumab (blue) binding CTLA-4 (green). From [[Protein Data Bank|PDB]] entry {{PDBe|5GGV}}.

<!-- Monoclonal antibody data -->
| mab_type = mab
| source = u
| target = [[CTLA-4]]

<!-- Clinical data -->
| pronounce = 
| tradename = Imjudo
| Drugs.com = {{drugs.com|monograph|tremelimumab-actl}}
| MedlinePlus = a622078
| DailyMedID = Tremelimumab
| pregnancy_AU = D
| pregnancy_AU_comment = <ref>{{cite web | title=Imjudo | website=Therapeutic Goods Administration (TGA) | date=29 June 2023 | url=https://www.tga.gov.au/resources/auspmd/imjudo | access-date=10 September 2023}}</ref>
| pregnancy_category = 
| routes_of_administration = [[Intravenous]]
| class = [[Antineoplastic agent]]
| ATC_prefix = L01
| ATC_suffix = FX20
| ATC_supplemental = 
| biosimilars = 

<!-- Legal status -->
| legal_AU = S4
| legal_AU_comment = <ref>{{cite web | title=Imjudo (AstraZeneca Pty Ltd) | website=Therapeutic Goods Administration (TGA) | date=28 July 2023 | url=https://www.tga.gov.au/resources/prescription-medicines-registrations/imjudo-astrazeneca-pty-ltd | access-date=10 September 2023 | archive-date=11 September 2023 | archive-url=https://web.archive.org/web/20230911061959/https://www.tga.gov.au/resources/prescription-medicines-registrations/imjudo-astrazeneca-pty-ltd | url-status=live }}</ref><ref>{{Cite web | url=https://www.tga.gov.au/resources/auspar/auspar-imjudo | title=AusPAR: Imjudo | website=www.tga.gov.au}}</ref>
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment = 
| legal_CA          = Rx-only
| legal_CA_comment  = <ref>{{cite web | title=Notice: Multiple additions to the Prescription Drug List (PDL) [2023-10-26] | website=[[Health Canada]] | date=26 October 2023 | url=https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/prescription-drug-list/notices-changes/multiple-additions-2023-10-26.html | access-date=3 January 2024 | archive-date=3 January 2024 | archive-url=https://web.archive.org/web/20240103061027/https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/prescription-drug-list/notices-changes/multiple-additions-2023-10-26.html | url-status=live }}</ref><ref>{{cite web | title=Summary Basis of Decision (SBD) for Imjudo | website=[[Health Canada]] | date=3 January 2024 | url=https://dhpp.hpfb-dgpsa.ca/review-documents/resource/SBD1704300260963 | access-date=17 January 2024 | archive-date=17 January 2024 | archive-url=https://web.archive.org/web/20240117090045/https://dhpp.hpfb-dgpsa.ca/review-documents/resource/SBD1704300260963 | url-status=live }}</ref><ref>{{cite web | title=Details for: Imjudo | website=[[Health Canada]] | date=23 October 2023 | url=https://dhpp.hpfb-dgpsa.ca/dhpp/resource/102967 | access-date=17 January 2024 | archive-date=17 January 2024 | archive-url=https://web.archive.org/web/20240117090049/https://dhpp.hpfb-dgpsa.ca/dhpp/resource/102967 | url-status=live }}</ref>
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment = 
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment = 
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK_comment = 
| legal_US = Rx-only
| legal_US_comment = <ref name="Imjudo FDA label">{{cite web | title=Imjudo- tremelimumab injection, solution | website=DailyMed | date=10 November 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6690679c-be2f-4588-a2e4-89fff74dd6be | access-date=18 November 2022 | archive-date=18 November 2022 | archive-url=https://web.archive.org/web/20221118234719/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6690679c-be2f-4588-a2e4-89fff74dd6be | url-status=live }}</ref>
| legal_EU = Rx-only
| legal_EU_comment = <ref name="Imjudo EPAR">{{cite web | title=Imjudo EPAR | website=[[European Medicines Agency]] (EMA) | date=9 December 2022 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/imjudo | access-date=2 March 2023 | archive-date=3 March 2023 | archive-url=https://web.archive.org/web/20230303071943/https://www.ema.europa.eu/en/medicines/human/EPAR/imjudo | url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref>
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment = 
| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->
| bioavailability = 
| protein_bound = 
| metabolism = 
| metabolites = 
| onset = 
| elimination_half-life = 
| duration_of_action = 
| excretion = 

<!-- Identifiers -->
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 745013-59-6
| CAS_supplemental = 
| PubChem = 
| IUPHAR_ligand = 8462
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = none
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB11771
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = QEN1X95CIX
| KEGG = D06657
| ChEBI = 
| ChEMBL = 
| NIAID_ChemDB = 
| PDB_ligand = 
| synonyms = tremelimumab-actl, ticilimumab, CP-675, CP-675,206

<!-- Chemical and physical data -->
| IUPAC_name = 
| C=6500 | H=9974 | N=1726 | O=2026 | S=52
| SMILES = 
| StdInChI = 
| StdInChI_comment = 
| StdInChIKey = 
| density = 
| density_notes = 
| melting_point = 
| melting_high = 
| melting_notes = 
| boiling_point = 
| boiling_notes = 
| solubility = 
| sol_units = 
| specific_rotation = 
}}

'''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).<ref name="Imjudo FDA label" /><ref name="Imjudo EPAR" /> 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).<ref name="Imjudo EPAR" />

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).<ref name="Imjudo EPAR" />

Tremelimumab was approved for medical use in the United States in October 2022,<ref name="Imjudo FDA label" /><ref>{{cite web | title=Drug Approval Package: Imjudo | website=U.S. [[Food and Drug Administration]] (FDA) | date=4 November 2022 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761289Orig1s000TOC.cfm | access-date=2 March 2023 | archive-date=3 March 2023 | archive-url=https://web.archive.org/web/20230303062855/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761289Orig1s000TOC.cfm | url-status=live }}</ref><ref>{{cite press release | title=Imjudo (tremelimumab) in combination with Imfinzi approved in the US for patients with unresectable liver cancer | website=AstraZeneca | date=26 October 2022 | url=https://www.astrazeneca.com/media-centre/press-releases/2022/imfinzi-and-imjudo-approved-in-advanced-liver-cancer.html | access-date=26 October 2022 | archive-date=24 October 2022 | archive-url=https://web.archive.org/web/20221024124047/https://www.astrazeneca.com/media-centre/press-releases/2022/imfinzi-and-imjudo-approved-in-advanced-liver-cancer.html | url-status=live }}</ref> and in the European Union in February 2023.<ref name="Imjudo EPAR" />

== Medical uses ==

Tremelimumab is [[indicated]], in combination with [[durvalumab]], for the treatment of adults with unresectable [[hepatocellular carcinoma]].<ref name="Imjudo FDA label" /><ref>{{cite web | title=FDA approves tremelimumab in combination with durvalumab and platinum- | website=U.S. [[Food and Drug Administration]] (FDA) | date=10 November 2022 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tremelimumab-combination-durvalumab-and-platinum-based-chemotherapy-metastatic-non | access-date=20 December 2022 | archive-date=20 December 2022 | archive-url=https://web.archive.org/web/20221220075834/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tremelimumab-combination-durvalumab-and-platinum-based-chemotherapy-metastatic-non | url-status=live }}</ref><ref name="Imjudo EPAR" />

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.<ref name="Imjudo EPAR" />

== 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.<ref name="Ribas">{{cite journal | vauthors = Ribas A | title = Tumor immunotherapy directed at PD-1 | journal = The New England Journal of Medicine | volume = 366 | issue = 26 | pages = 2517–9 | date = June 2012 | pmid = 22658126 | doi = 10.1056/NEJMe1205943 | doi-access =  | title-link = doi }}</ref>

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.<ref name="Tremelimumab NCI">{{cite web | title=Tremelimumab | website=National Cancer Institute | url=https://www.cancer.gov/publications/dictionaries/cancer-drug | access-date=27 October 2022 | archive-date=10 August 2019 | archive-url=https://web.archive.org/web/20190810012312/https://www.cancer.gov/publications/dictionaries/cancer-drug | url-status=live }} {{PD-notice}}</ref> 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.<ref name="Tremelimumab NCI" />

Unlike [[Ipilimumab]] (another fully human [[anti-CTLA-4]] monoclonal antibody), which is an [[IgG]]1 isotype, tremelimumab is an IgG2 isotype.<ref name="pmid19088949">{{cite journal |vauthors=Tomillero A, Moral MA | title = Gateways to clinical trials | journal = Methods Find Exp Clin Pharmacol | volume = 30 | issue = 8 | pages = 643–72 |date=October 2008 | pmid = 19088949 | doi = 10.1358/mf.2008.30.5.1236622 }}</ref><ref name="pmid19052265">{{cite journal | author = Poust J | title = Targeting metastatic melanoma | journal = Am J Health Syst Pharm | volume = 65 | issue = 24 Suppl 9 | pages = S9–S15 |date=December 2008 | pmid = 19052265 | doi = 10.2146/ajhp080461 }}</ref>

== History ==
Previously in development by [[Pfizer]],<ref name=PR>{{cite news|title=Pfizer Announces Discontinuation of Phase III Clinical Trial for Patients with Advanced Melanoma|url=http://www.pfizer.com/news/press-release/press-release-detail/pfizer_announces_discontinuation_of_phase_iii_clinical_trial_for_patients_with_advanced_melanoma|access-date=5 December 2015|publisher=Pfizer.com|date=1 April 2008|archive-date=8 December 2015|archive-url=https://web.archive.org/web/20151208142136/http://www.pfizer.com/news/press-release/press-release-detail/pfizer_announces_discontinuation_of_phase_iii_clinical_trial_for_patients_with_advanced_melanoma|url-status=live}}</ref> it is in investigation by [[MedImmune]], a wholly owned subsidiary of [[AstraZeneca]].<ref>[https://www.azimmuno-oncology.com/ctla-4-inhibition#Tremelimumab Mechanism of Pathway: CTLA-4 Inhibition]{{Dead link|date=April 2019 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>

=== Clinical trials ===

=== Melanoma ===
Phase I and II [[clinical studies]] in metastatic [[melanoma]] showed some responses.<ref>{{cite journal | vauthors = Reuben JM, Lee BN, Li C, Gomez-Navarro J, Bozon VA, Parker CA, Hernandez IM, Gutierrez C, Lopez-Berestein G, Camacho LH | title = Biologic and immunomodulatory events after CTLA-4 blockade with ticilimumab in patients with advanced malignant melanoma | journal = Cancer | volume = 106 | issue = 11 | pages = 2437–44 | date = June 2006 | pmid = 16615096 | doi = 10.1002/cncr.21854 | doi-access = free | title-link = doi }}</ref> However, based on early interim analysis of phase III data, [[Pfizer]] designated tremelimumab as a failure and terminated the trial in April 2008.<ref name=PR/><ref>{{cite journal | vauthors = 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 | title = Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma | journal = Journal of Clinical Oncology | volume = 31 | issue = 5 | pages = 616–22 | date = February 2013 | pmid = 23295794 | pmc = 4878048 | doi = 10.1200/JCO.2012.44.6112 | doi-access = free | title-link = doi }}</ref>

However, within a year, the survival curves showed separation of the treatment and control groups.<ref>{{cite journal | vauthors = Marshall MA, Ribas A, Huang B |title = Evaluation of baseline serum C-reactive protein (CRP) and benefit from tremelimumab compared to chemotherapy in first-line melanoma |journal = Journal of Clinical Oncology |volume = 28 |issue = 15S |pages = 2609 |date = May 2010 |doi = 10.1200/jco.2010.28.15_suppl.2609 }}</ref>

=== Mesothelioma ===
Although it was designated in April 2015 as [[orphan drug]] status in [[mesothelioma]],<ref>{{cite web | vauthors = Duff J | date = 17 April 2015 | work =  Mesothelioma Cancer Alliance | title = FDA Grants AstraZeneca's Tremelimumab Orphan Drug Status for Mesothelioma | url = http://www.mesothelioma.com/news/2015/04/fda-grants-astrazenecas-tremelimumab-orphan-drug-status-for-mesothelioma.htm | archive-url = https://web.archive.org/web/20160731101622/http://www.mesothelioma.com/news/2015/04/fda-grants-astrazenecas-tremelimumab-orphan-drug-status-for-mesothelioma.htm | archive-date=31 July 2016 }}</ref> 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.<ref>{{cite web |url=http://www.fdanewsalert.com/astrazeneca-fails-mesothelioma-drug-trial/8517952/ |title=Tremelimumab Fails Mesothelioma Drug Trial | work = FDA News Alert | date= 29 February 2016 | vauthors = Krassenstein B |access-date=6 March 2016 |archive-url=https://web.archive.org/web/20160306150651/http://www.fdanewsalert.com/astrazeneca-fails-mesothelioma-drug-trial/8517952/ |archive-date=6 March 2016 |url-status=dead }}</ref><ref>{{cite web  | vauthors = McKee S | date = 1 March 2016 | work = PharmaTimes |url=http://www.pharmatimes.com/Article/16-03-01/AZ_tremelimumab_fails_in_mesothelioma_trial.aspx |title=AZ' tremelimumab fails in mesothelioma trial |access-date=6 March 2016 |archive-date=6 March 2016 |archive-url=https://web.archive.org/web/20160306114327/http://www.pharmatimes.com/Article/16-03-01/AZ_tremelimumab_fails_in_mesothelioma_trial.aspx |url-status=live }}</ref>

=== 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]].<ref>{{cite web | url=http://www.fiercebiotech.com/biotech/astrazeneca-hit-by-mystic-lung-cancer-pfs-failure | vauthors=Adams B | date=27 July 2017 | title=AstraZeneca's immuno-oncology combo fails crucial Mystic trial in lung cancer | work=FierceBiotech | access-date=23 August 2017 | archive-date=17 May 2022 | archive-url=https://web.archive.org/web/20220517112749/https://www.fiercebiotech.com/biotech/astrazeneca-hit-by-mystic-lung-cancer-pfs-failure | url-status=live }}</ref> 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.<ref>{{cite press release | date = 27 July 2017 | work = AstraZeneca | url = https://www.astrazeneca.com/media-centre/press-releases/2017/astrazeneca-reports-initial-results-from-the-ongoing-mystic-trial-in-stage-iv-lung-cancer-27072017.html | title = AstraZeneca reports initial results from the ongoing MYSTIC trial in Stage IV lung cancer | access-date = 23 August 2017 | archive-date = 28 August 2021 | archive-url = https://web.archive.org/web/20210828065958/https://www.astrazeneca.com/media-centre/press-releases/2017/astrazeneca-reports-initial-results-from-the-ongoing-mystic-trial-in-stage-iv-lung-cancer-27072017.html | url-status = live }}</ref>

== 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.<ref name="Imjudo: Pending EC decision" /> The applicant for this medicinal product is AstraZeneca AB.<ref name="Imjudo: Pending EC decision">{{cite web | title=Imjudo: Pending EC decision | website=[[European Medicines Agency]] (EMA) | date=15 December 2022 | url=https://www.ema.europa.eu/en/medicines/human/summaries-opinion/imjudo | access-date=16 December 2022 | archive-date=16 December 2022 | archive-url=https://web.archive.org/web/20221216225505/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/imjudo | url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> Tremelimumab was approved for medical use in the European Union in February 2023.<ref name="Imjudo EPAR" /><ref>{{cite web | title=Imjudo Product information | website=Union Register of medicinal products | date=23 February 2023 | url=https://ec.europa.eu/health/documents/community-register/html/h1713.htm | access-date=2 March 2023 | archive-date=27 February 2023 | archive-url=https://web.archive.org/web/20230227113459/https://ec.europa.eu/health/documents/community-register/html/h1713.htm | url-status=live }}</ref>

=== Names ===
Tremelimumab is the [[international nonproprietary name]] (INN).<ref name=WHORecList59>{{cite journal | vauthors = ((World Health Organization)) | year = 2008 | title = International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 59 | journal = WHO Drug Information | volume = 22 | issue = 1 | page = | hdl = 10665/74120  | hdl-access = free | author-link = World Health Organization }}</ref>

== References ==
{{Reflist}}

{{Targeted cancer therapeutic agents}}
{{Monoclonals for tumors}}
{{Monoclonals for immune system}}
{{Immunosuppressants}}
{{Portal bar | Medicine}}
{{Authority control}}

[[Category:Drugs developed by Pfizer]]
[[Category:Drugs developed by AstraZeneca]]
[[Category:Orphan drugs]]
[[Category:Monoclonal antibodies for tumors]]