NAV

Tremelimumab

Identification

Summary

Tremelimumab is an anti-CTLA-4 antibody used to treat unresectable hepatocellular carcinoma in combination with durvalumab.

Brand Names
Imjudo
Generic Name
Tremelimumab
DrugBank Accession Number
DB11771
Background

Tremelimumab, formerly known as ticilimumab, is a fully human IgG2 monoclonal antibody directed against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). CTLA-4 is a cell surface receptor expressed on activated T cells to act as a negative regulator for T cells.2 By binding to CTLA-4, tremelimumab enhances T cell-mediated killing of tumours and reduces tumour growth.2,8 Because CTLA-4 is an immune checkpoint that plays a vital role in regulating T cell-mediated immune response, tremelimumab is considered an immune checkpoint inhibitor, which is an emerging cancer immunotherapy drug class.1

Tremelimumab was first approved by the FDA in October 2022 to be used in combination with durvalumab to treat hepatocellular carcinoma.8 It is also being investigated in other cancers, such as colon cancer, pancreatic cancer, non-small cell lung cancer (NSCLC), and malignant melanoma.2,3

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
C6500H9974N1726O2026S52
Protein Average Weight
149000.0 Da (approximate)
Sequences
>Tremelimumab heavy chain
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNKYY
ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDPRGATLYYYYYGMDVWGQGTT
VTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
VLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVA
GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQF
NSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSRE
EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSR
WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>Tremelimumab light chain
DIQMTQSPSSLSASVGDRVTITCRASQSINSYLDWYQQKPGKAPKLLIYAASSLQSGVPS
RFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPFTFGPGTKVEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
References:
  1. KEGG DRUG: Tremelimumab [Link]
Download FASTA Format
Synonyms
  • Ticilimumab
  • Tremelimumab
External IDs
  • CP 675,206
  • CP-675
  • CP-675,206
  • CP-675206

Pharmacology

Indication

Tremelimumab is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma in combination with durvalumab.8 It is also indicated in combination with durvalumab and platinum-based chemotherapy for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with no sensitizing epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.10

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Tremelimumab is a cytotoxic agent that works to decrease tumour growth.8 It binds to its target, human CTLA-4, with high selectivity 2 and subnanomolar affinity.1 Tremelimumab caused increased IL-2 production in a dose-dependent manner in ex-vivo blood stimulation assays using peripheral blood mononuclear cells (PBMCs) from healthy volunteers and patients with cancer, indicating that tremelimumab stimulated T cell-mediated cytotoxicity. Tremelimumab also increased the proliferation of effector T cells.1

In vitro, there was no evidence of nonspecific cytokine release induced by tremelimumab or drug binding to Fc receptors.6,7

Mechanism of action

T cell activation is influenced by several processes. T cell receptors (TCR), which are expressed on T cells, bind to the cognate antigen processed and presented by major histocompatibility complex (MHC) expressed on antigen-presenting cells (APC).5 This interaction generates a TCR signal to activate T cells. In addition to the TCR signal, optimal T cell activation requires a costimulatory signal, produced when CD80 and CD86, expressed on the surface of APCs, bind to receptors expressed on T cells.1 CD80 and CD86 are also referred to together as B7 molecules.4 In response to these signals, activated T cells can be further differentiated into specific T cell subtypes with specialized functions.5

Immune checkpoints are proteins that control the intensity and duration of T cell activation and response. CD28 and CTLA-4 are homologous receptors expressed on CD4+ and CD8+ T cell surface.4 These immune checkpoints have opposing regulatory functions on T cell activity: CD28 is a positive regulator of T cell activity, while CTLA-4 is a negative regulator suppressing T cell activation and proliferation, as well as IL-2 gene transcription.1,7 B7 molecules act as ligands to both of these receptors,4 and the balance between CD28 and CTLA-4 expression and signalling influence the extent of T cell activation. In cancer immunotherapy, CTLA-4 has been investigated as a therapeutic target as blocking this receptor can enhance the activation of tumour-specific T cells, allowing them to exert cytotoxic effects on tumour cells.1

Tremelimumab is an antibody directed against CTLA-4. By binding to CTLA-4, tremelimumab blocks the interaction of CTLA-4 with its ligands, CD80 and CD86, limiting its negative regulatory effect on T cell activation. Inhibition of CTLA-4 leads to increased proliferation of T cells in tumours and promotes T cell-mediated cytotoxicity.8

TargetActionsOrganism
ACytotoxic T-lymphocyte protein 4
inhibitor
antibody
Humans
Absorption

In patients with solid tumours who received tremelimumab doses 1 mg/kg, 3 mg/kg, and 10 mg/kg (1- to 10-times the approved recommended dosage) once every four weeks for four doses, the AUC of tremelimumab increased proportionally and steady-state was achieved at approximately 12 weeks.8

Volume of distribution

The geometric mean (% coefficient of variation [CV%]) of tremelimumab for central (V1) and peripheral (V2) volume of distribution was 3.45 (24%) and 2.66 (34%) L, respectively.8

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

The geometric mean (CV%) terminal half-life of tremelimumab was 16.9 days (19%) after a single dose and 18.2 days (19%) during steady-state.8

Clearance

The geometric mean (CV%) clearance of tremelimumab was 0.286 L/day (32%) after a single dose and 0.263 L/day (32%) during steady-state.8

Adverse Effects
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Toxicity

There is limited information regarding the acute toxicity profile and overdosage of tremelimumab. The maximum tolerated dose in non-human primates was 100 mg/kg.9

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
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interactions in your software
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Tremelimumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Tremelimumab.
AducanumabThe risk or severity of adverse effects can be increased when Tremelimumab is combined with Aducanumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Tremelimumab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Tremelimumab.
AmivantamabThe risk or severity of adverse effects can be increased when Tremelimumab is combined with Amivantamab.
AnifrolumabThe risk or severity of adverse effects can be increased when Tremelimumab is combined with Anifrolumab.
AnsuvimabThe risk or severity of adverse effects can be increased when Tremelimumab is combined with Ansuvimab.
Anthrax immune globulin humanThe risk or severity of adverse effects can be increased when Anthrax immune globulin human is combined with Tremelimumab.
Antilymphocyte immunoglobulin (horse)The risk or severity of adverse effects can be increased when Antilymphocyte immunoglobulin (horse) is combined with Tremelimumab.
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Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ImjudoInjection, solution25 mg/1.25mLIntravenousAstraZeneca Pharmaceuticals LP2022-10-21Not applicableUS flag
ImjudoInjection, solution300 mg/15mLIntravenousAstraZeneca Pharmaceuticals LP2022-10-21Not applicableUS flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
QEN1X95CIX
CAS number
745013-59-6

References

General References
  1. Tarhini AA: Tremelimumab: a review of development to date in solid tumors. Immunotherapy. 2013 Mar;5(3):215-29. doi: 10.2217/imt.13.9. [Article]
  2. Authors unspecified: Tremelimumab. Drugs R D. 2010;10(2):123-32. doi: 10.2165/11584530-000000000-00000. [Article]
  3. Arru C, De Miglio MR, Cossu A, Muroni MR, Carru C, Zinellu A, Paliogiannis P: Durvalumab Plus Tremelimumab in Solid Tumors: A Systematic Review. Adv Ther. 2021 Jul;38(7):3674-3693. doi: 10.1007/s12325-021-01796-6. Epub 2021 Jun 8. [Article]
  4. Rowshanravan B, Halliday N, Sansom DM: CTLA-4: a moving target in immunotherapy. Blood. 2018 Jan 4;131(1):58-67. doi: 10.1182/blood-2017-06-741033. Epub 2017 Nov 8. [Article]
  5. Hwang JR, Byeon Y, Kim D, Park SG: Recent insights of T cell receptor-mediated signaling pathways for T cell activation and development. Exp Mol Med. 2020 May;52(5):750-761. doi: 10.1038/s12276-020-0435-8. Epub 2020 May 21. [Article]
  6. Ribas A: Clinical development of the anti-CTLA-4 antibody tremelimumab. Semin Oncol. 2010 Oct;37(5):450-4. doi: 10.1053/j.seminoncol.2010.09.010. [Article]
  7. Ribas A, Hanson DC, Noe DA, Millham R, Guyot DJ, Bernstein SH, Canniff PC, Sharma A, Gomez-Navarro J: Tremelimumab (CP-675,206), a cytotoxic T lymphocyte associated antigen 4 blocking monoclonal antibody in clinical development for patients with cancer. Oncologist. 2007 Jul;12(7):873-83. doi: 10.1634/theoncologist.12-7-873. [Article]
  8. FDA Approved Drug Products: IMJUDO (tremelimumab-actl) injection, for intravenous use [Link]
  9. Pfizer: Tremelimumab MSDS [Link]
  10. FDA Approved Drug Products: IMJUDO (tremelimumab-actl) injection, for intravenous use (November 2022) [Link]
PubChem Substance
347911239
RxNav
2619313
Wikipedia
Tremelimumab

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentNon-Small Cell Lung Cancer (NSCLC)2
3Active Not RecruitingTreatmentNon-small Cell Lung Carcinoma (Adenocarcinoma)2
3Active Not RecruitingTreatmentSmall Cell Lung Cancer (SCLC)1
3Active Not RecruitingTreatmentSmall Cell Lung Carcinoma, Extensive Disease1
3Active Not RecruitingTreatmentUrothelial Cancer1
3CompletedTreatmentAdvanced Malignant Solid Tumor1
3CompletedTreatmentMelanoma1
3CompletedTreatmentRecurrent or Metastatic PD-L1-positive or -Negative Squamous Cell Carcinoma of the Head and Neck (SCCHN)1
3CompletedTreatmentSquamous Cell Carcinoma of the Head and Neck (SCCHN)1
3Not Yet RecruitingTreatmentHepatocellular Carcinoma1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionIntravenous25 mg/1.25mL
Injection, solutionIntravenous300 mg/15mL
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

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Details1. Cytotoxic T-lymphocyte protein 4
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Antibody
General Function
Not Available
Specific Function
Inhibitory receptor acting as a major negative regulator of T-cell responses. The affinity of CTLA4 for its natural B7 family ligands, CD80 and CD86, is considerably stronger than the affinity of t...
Gene Name
CTLA4
Uniprot ID
P16410
Uniprot Name
Cytotoxic T-lymphocyte protein 4
Molecular Weight
24655.63 Da
References
  1. Ribas A, Hanson DC, Noe DA, Millham R, Guyot DJ, Bernstein SH, Canniff PC, Sharma A, Gomez-Navarro J: Tremelimumab (CP-675,206), a cytotoxic T lymphocyte associated antigen 4 blocking monoclonal antibody in clinical development for patients with cancer. Oncologist. 2007 Jul;12(7):873-83. doi: 10.1634/theoncologist.12-7-873. [Article]
  2. Kyriakidis I, Vasileiou E, Rossig C, Roilides E, Groll AH, Tragiannidis A: Invasive Fungal Diseases in Children with Hematological Malignancies Treated with Therapies That Target Cell Surface Antigens: Monoclonal Antibodies, Immune Checkpoint Inhibitors and CAR T-Cell Therapies. J Fungi (Basel). 2021 Mar 5;7(3). pii: jof7030186. doi: 10.3390/jof7030186. [Article]
  3. FDA Approved Drug Products: IMJUDO (tremelimumab-actl) injection, for intravenous use [Link]

Drug created at October 20, 2016 20:46 / Updated at December 01, 2022 11:27