Identification

Summary

Tebentafusp is a bispecific gp100 peptide-HLA-directed CD3 T cell engager used to treat unresectable or metastatic uveal melanoma.

Brand Names
Kimmtrak
Generic Name
Tebentafusp
DrugBank Accession Number
DB15283
Background

Tebentafusp is a gp100 peptide-HLA-directed CD3 T cell engager.5 It is a bispecific, fusion protein and first-in-class drug of immune-mobilizing monoclonal T cell receptors against cancer (ImmTACs), a recently developed cancer immunotherapy with a novel mechanism of action. ImmTACs bind to target cancer cells that express a specific antigen of interest and recruit cytotoxic T cells to lyse the cells, such as melanocytes.1,2

Uveal melanoma is a rare ocular tumour with often poor prognosis and limited treatment options. Even after surgical ablation or removal of the ocular tumour, almost 50% of patients with uveal melanoma develop metastatic disease.1 On January 26, 2022, tebentafusp was first approved by the FDA for the treatment of HLA-A*02:01-positive adults with unresectable or metastatic uveal melanoma. This approval marks the first bispecific T cell engager to be approved by the FDA to treat a solid tumour and being the first and only therapy for the treatment of unresectable or metastatic uveal melanoma to be approved by the FDA.5 Tebentafusp was subsequently approved for the same indication in the EU in April 2022.7

Type
Biotech
Groups
Approved, Investigational
Synonyms
  • Tebentafusp
External IDs
  • IMCGP100

Pharmacology

Indication

Tebentafusp is indicated for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma.4

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Associated Conditions
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Pharmacodynamics

Tebentafusp is novel immunotherapy that causes cytotoxicity of cancer cells. Tebentafusp increased the serum levels of cytokines (IFN-γ, TNFα, IL-2, IL-6, IL-10 and IL-1RA) and chemokines (CXCL9, CXCL10, CXCL11, hepatocyte growth factor, and monocyte chemoattractant protein-1) during the first three doses. The levels of cytokines and chemokines peaked between eight to 24 hours after treatment, and levels returned to baseline before subsequent doses. In subsequent treatment cycles, cytokine elevation occurred in fewer patients with lesser intensity than the first three doses. Tebentafusp also reduced lymphocyte counts after the first three doses, which returned to baseline before subsequent doses.4 In phase III clinical trials, patients treated with tebentafusp showed a better overall survival rate compared to pembrolizumab, ipilimumab, or dacarbazine.5

Mechanism of action

Glycoprotein 100 (gp100) is a transmembrane glycoprotein highly expressed in melanoma cells and weakly expressed by normal melanocytes or other tissues. Gp100 is presented as a human leukocyte antigen (HLA)-peptide complex on the cell surface. Gp100 has a particularly high affinity for the HLA-A subtype HLA-A*02:01.1,2 HLAs are part of a protein complex that normally regulates immune function: natural T cell responses are initiated by the interaction between the T-cell receptor (TCR) and its peptide antigen, such as gp100, presented by HLA on the surface of a target cell.3

Tebentafusp is a bispecific gp100 peptide-HLA-A02:01 directed T cell receptor CD3 T cell engager. It consists of a TCR targeting domain - or a TCR arm - fused to a single-chain variable fragment (scFv) anti-CD3 effector domain.1 The TCR arm binds to a gp100 peptide bound to HLA-A02:01 on the uveal melanoma tumour cell surface. The anti-CD3 effector domain of tebentafusp engages and activates CD3+ T cells to inflammatory cytokines and cytolytic proteins, which results in direct lysis of uveal melanoma tumour cells.4 The anti-CD3 fragment of the drug has a lower affinity, so the T cells are not stimulated unless tebentafusp has detected gp100.2 As the HLA-A02:01 subtype is not present in all individuals,2 tebentafusp is only effective in HLA-A02:01-positive patients.4

TargetActionsOrganism
AMelanocyte protein PMEL
binder
Humans
Absorption

After a single dose administration, Cmax and AUC0-7d increased dose-proportionally from 20 to 68 mg (0.3 to 1 times the approved recommended dose). Following administration of the approved recommended dosage in patients with metastatic uveal melanoma, the steady-state geometric mean (% CV) Cmax of tebentafusp was 13 ng/mL (34.6%) and AUC0-7d was 4.6 ng.day/mL (23%) with no accumulation.4

Volume of distribution

The geometric mean (%CV) steady-state volume of distribution is 7.56 L (24%).4

Protein binding

There is no information available.

Metabolism

Tebentafusp is expected to be catabolized into small peptides and amino acids.4

Route of elimination

There is no information available.

Half-life

The median terminal half-life is 7.5 hours, with a range of 6.8 to 7.5 hours.4

Clearance

The geometric mean clearance (%CV) of tebentafusp is 16.4 L/d (24.5%).4

Adverse Effects
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Toxicity

There is limited information regarding the LD50 and overdose of tebentafusp.

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
Darbepoetin alfaThe risk or severity of Thrombosis can be increased when Darbepoetin alfa is combined with Tebentafusp.
ErythropoietinThe risk or severity of Thrombosis can be increased when Erythropoietin is combined with Tebentafusp.
Methoxy polyethylene glycol-epoetin betaThe risk or severity of Thrombosis can be increased when Methoxy polyethylene glycol-epoetin beta is combined with Tebentafusp.
PeginesatideThe risk or severity of Thrombosis can be increased when Peginesatide is combined with Tebentafusp.
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Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
KimmtrakInjection, solution, concentrate100 mcg/0.5mLIntravenousImmunocore Ireland Limited2022-05-04Not applicableEU flag
KimmtrakSolution100 mcg / 0.5 mLIntravenousImmunocore Ireland LimitedNot applicableNot applicableCanada flag
KimmtrakInjection, solution, concentrate100 ug/0.5mLIntravenousImmunocore Commercial LLC2022-01-26Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
N658GY6L3E
CAS number
1874157-95-5

References

General References
  1. Damato BE, Dukes J, Goodall H, Carvajal RD: Tebentafusp: T Cell Redirection for the Treatment of Metastatic Uveal Melanoma. Cancers (Basel). 2019 Jul 11;11(7). pii: cancers11070971. doi: 10.3390/cancers11070971. [Article]
  2. Martinez-Perez D, Vinal D, Solares I, Espinosa E, Feliu J: Gp-100 as a Novel Therapeutic Target in Uveal Melanoma. Cancers (Basel). 2021 Nov 27;13(23). pii: cancers13235968. doi: 10.3390/cancers13235968. [Article]
  3. Middleton MR, McAlpine C, Woodcock VK, Corrie P, Infante JR, Steven NM, Evans TRJ, Anthoney A, Shoushtari AN, Hamid O, Gupta A, Vardeu A, Leach E, Naidoo R, Stanhope S, Lewis S, Hurst J, O'Kelly I, Sznol M: Tebentafusp, A TCR/Anti-CD3 Bispecific Fusion Protein Targeting gp100, Potently Activated Antitumor Immune Responses in Patients with Metastatic Melanoma. Clin Cancer Res. 2020 Nov 15;26(22):5869-5878. doi: 10.1158/1078-0432.CCR-20-1247. Epub 2020 Aug 18. [Article]
  4. FDA Approved Drug Products: KIMMTRAK (tebentafusp-tebn) injection, for intravenous use [Link]
  5. BioSpace News: Immunocore announces FDA approval of KIMMTRAK® (tebentafusp-tebn) for the treatment of unresectable or metastatic uveal melanoma [Link]
  6. NIH NCATS Inxight Drugs: TEBENTAFUSP [Link]
  7. EMA Summary of Product Characteristics: Kimmtrak (tebentafusp) concentrate for intravenous infusion [Link]
RxNav
2590743
Wikipedia
Immunocore

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2Active Not RecruitingTreatmentUveal Melanoma1
2RecruitingDiagnosticMelanoma / Uveal Melanoma1
2TerminatedTreatmentMelanoma, Malignant1
1CompletedTreatmentMelanoma, Malignant1
1, 2Active Not RecruitingTreatmentUveal Melanoma1
1, 2RecruitingTreatmentMelanoma, Malignant1
0CompletedTreatmentAdvanced Disease / Melanoma / Unresectable1
Not AvailableAvailableNot AvailableUveal Melanoma1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solution, concentrateIntravenous100 mcg/0.5mL
Injection, solution, concentrateIntravenous100 ug/0.5mL
SolutionIntravenous100 mcg / 0.5 mL
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
General Function
Plays a central role in the biogenesis of melanosomes. Involved in the maturation of melanosomes from stage I to II. The transition from stage I melanosomes to stage II melanosomes involves an elongation of the vesicle, and the appearance within of distinct fibrillar structures. Release of the soluble form, ME20-S, could protect tumor cells from antibody mediated immunity.
Specific Function
Identical protein binding
Gene Name
PMEL
Uniprot ID
P40967
Uniprot Name
Melanocyte protein PMEL
Molecular Weight
70254.63 Da
References
  1. Damato BE, Dukes J, Goodall H, Carvajal RD: Tebentafusp: T Cell Redirection for the Treatment of Metastatic Uveal Melanoma. Cancers (Basel). 2019 Jul 11;11(7). pii: cancers11070971. doi: 10.3390/cancers11070971. [Article]
  2. Martinez-Perez D, Vinal D, Solares I, Espinosa E, Feliu J: Gp-100 as a Novel Therapeutic Target in Uveal Melanoma. Cancers (Basel). 2021 Nov 27;13(23). pii: cancers13235968. doi: 10.3390/cancers13235968. [Article]
  3. Middleton MR, McAlpine C, Woodcock VK, Corrie P, Infante JR, Steven NM, Evans TRJ, Anthoney A, Shoushtari AN, Hamid O, Gupta A, Vardeu A, Leach E, Naidoo R, Stanhope S, Lewis S, Hurst J, O'Kelly I, Sznol M: Tebentafusp, A TCR/Anti-CD3 Bispecific Fusion Protein Targeting gp100, Potently Activated Antitumor Immune Responses in Patients with Metastatic Melanoma. Clin Cancer Res. 2020 Nov 15;26(22):5869-5878. doi: 10.1158/1078-0432.CCR-20-1247. Epub 2020 Aug 18. [Article]
  4. FDA Approved Drug Products: KIMMTRAK (tebentafusp-tebn) injection, for intravenous use [Link]

Drug created at May 20, 2019 15:08 / Updated at June 27, 2022 18:22