Tasonermin

Identification

Summary

Tasonermin is a tumor necrosis factor alpha used along with surgery to remove soft tissue sarcomas of the limbs.

Brand Names

Beromun

Generic Name

Tasonermin

DrugBank Accession Number

DB11626

Background

Tasonermin is recombinant soluble form tumor necrosis factor α produced via Escherichia coli cell culture. It was approved for use by the European Medicines Agency in April of 1999 for use as an adjunt to surgery for the subsequent removal of the tumor and in palliative care for irresectable soft tissue sarcoma of the limbs as the product Beromun. It is administered with Melphalan via mild hyperthermic isolated limb perfusion.

Type

Biotech

Groups

Approved

Biologic Classification

Protein Based Therapies
Other protein based therapies

Protein Structure

Protein Chemical Formula: Not Available
Protein Average Weight: 17724.0 Da

Sequences

> Tasonermin homotrimer subunit, 157 amino acid sequence
VRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELRDNQLVVPSEGLYLIYS
QVLFKGQGCPSTHVLLTHTISRIAVSYQTKVNLLSAIKSPCQRETPEGAEAKPWYEPIYL
GGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGIIAL

Download FASTA Format

Synonyms

Tasonermin
Tasonermina
Tumor necrosis factor, soluble form, nonglycosylated

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Pharmacology

Indication

For use in adults as an adjunct to surgery for subsequent removal of the tumour so as to prevent or delay amputation, or in palliative care, for irresectable soft tissue sarcoma of the limbs ^Label. Used in combination with melphalan via mild hyperthermic isolated limb perfusion.

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Used as adjunct in combination to treat	Irresectable soft tissue sarcoma of the limb	Regimen in combination with: Melphalan (DB01042)	••••••••••••	•••••		•••••••••• ••••••• ••• ••••••••

Contraindications & Blackbox Warnings

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Pharmacodynamics

Tasonermin is thought to contribute to the destruction of tumor tissue via several direct and indirect effects ^Label.

Tasonermin directly inhibits cell proliferation in a variety of cancer cells. It also modifies endothelial cell morphology and reduces their proliferation in tumor microvasculature. Modification of the expression of cell adhesion proteins, proteins affecting coagulation, interleukins, and hematopoietic growth factors favors a procoagulant state resulting in microvascular thrombosis. These changes also increase infiltration of the tumor tissue by leukocytes.

Monocytes, macrophages, and granulocytes are activated allowing better adherence to the endothelium and subjecting the tumor cells to phagocytosis and respiratory bursts as well as producing degranulation of immune cells to further enhance inflammatory activity. Active antigen presenting cells are able to activate and induce proliferation of T- and B-lymphocyte cells to allow the adaptive immune system to contribute to tumor cell damage.

These changes lead to hemorraghic necrosis of the tumor.

Mechanism of action

Since tasonermin is recombinant TNF-α, it functions exactly as endogenous TNF-α does. The direct cytotoxic effect of TNF-α is mediated by TNF-α receptor 1 ². The bound receptor activates the well-reviewed death receptor pathway involving the activation of initiator caspases 8 and 9 then ultimately ending in the activation of effector caspase 3 which begins the process of apoptosis.

The effect on tumor vasculature is mediated by the inflammatory signalling pathway of TNF-α, the NFκB pathway ². This pathway is also activated by TNFR1 when bound to TNFα. The NFκB transcription factor increases expression of proteins in vascular endothelial cells. These proteins include cell adhesion molecules, inflammatory mediators like prostaglandins and interleukins, and growth factors ⁴. TNF-&alpha also increases the expression of inducible nitric oxide synthase via this pathway which contributes to the generation of reactive nitrogen species ³. These species are able to damage cells in the tumor and microvasculature.

The cytokines produced from NFκB activation and TNF-&aplha; itself serve to activate the cells of the immune system which further damage tumor cells with respiratory bursts, phagocytosis and subsequent breakdown of the cell, and release of cytotoxic enzymes. The antigen presenting cells which phagocytose the tumor cells are able to activate lymphocytes and allow the adaptive immune system to further damage the tumor tissue ⁵.

Target	Actions	Organism
ATumor necrosis factor receptor superfamily member 1A	agonist	Humans
UTumor necrosis factor receptor superfamily member 1B	agonist	Humans

Absorption

No absorption data is available. No enteral route formulation exists for tasonermin.

Volume of distribution

The estimated volume of distribution varies with the dose administered with intravenous doses of 35 μg/m² and 150 μg/m² producing values of 55 L and 17 L respectively ⁶.

Protein binding

No data is available on tasonermin binding to plasma proteins.

Metabolism

No metabolism data is available. Tasonermin is assumed to be broken down similarly to other proteins in systemic circulation.

Route of elimination

No data is available on route of elimination.

Half-life

Tasonermin has a terminal half life of 20-30 min at doses of 150 μg/m² ⁶. This value increases as dosage increases.

Clearance

Clearance was estimated to be 2 L/min and 0.5 L/min after intravenous doses of 35 μg/m² and 150 μg/m² respectively ⁶. This value decreases as dosage increases.

Adverse Effects

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Toxicity

In addition to its intended cytotoxic effects, tasonermin produces secondary adverse effects.

Studies in mice, rats, dogs, monkeys, and rabbits observed hematological changes including anemia, increased hematocrit, and changes in leukocyte and platelet counts dependent on species and treatment duration ^Label.

Tasonermin also produces decreases in blood pressure. Increases in heart rate and reductions in cardiac contractility have been noted in some studies.

Increased liver enzymes suggest altered liver function as a result of tasonermin administration. Changes in kidney function have also been observed including increased water and sodium excretion as well as increased serum urea and creatinine.

The only study to determine a no observable adverse effect level found the value to be 0.1 μg/kg in monkeys during a 7-day course of tasonermin.

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.
Not Available
Food Interactions: No interactions found.

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Beromun	Injection, powder, for solution	1 mg/5ml		Belpharma S.A.	2016-09-07	Not applicable

Chemical Identifiers

UNII: 23CA79S88F
CAS number: 94948-59-1

References

General References

Collins T, Read MA, Neish AS, Whitley MZ, Thanos D, Maniatis T: Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers. FASEB J. 1995 Jul;9(10):899-909. [Article]
Wajant H, Pfizenmaier K, Scheurich P: Tumor necrosis factor signaling. Cell Death Differ. 2003 Jan;10(1):45-65. doi: 10.1038/sj.cdd.4401189. [Article]
Zhang H, Park Y, Wu J, Chen Xp, Lee S, Yang J, Dellsperger KC, Zhang C: Role of TNF-alpha in vascular dysfunction. Clin Sci (Lond). 2009 Feb;116(3):219-30. doi: 10.1042/CS20080196. [Article]
Pate M, Damarla V, Chi DS, Negi S, Krishnaswamy G: Endothelial cell biology: role in the inflammatory response. Adv Clin Chem. 2010;52:109-30. [Article]
Brunton LL, Hilal-Dandan R, Knollmann BC. eds (2018). Goodman & Gilman's: The Pharmacological Basis of Therapeutics (13th ed.). McGraw-Hill Education. [ISBN:978-1-25-958473-2]
EMA: Tasonermin Scientific Discussion [Link]
EMA Summary of Product Characteristics: Beromun (tasonermin) powder for solution for infusion [Link]

External Links

RxNav: 283746
Wikipedia: Tumor_necrosis_factor

FDA label

Download (193 KB)

MSDS

Download (31.8 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
1	Withdrawn	Treatment	Lymphoma / Solid Tumors	1
Not Available	Completed	Not Available	Inflammation / Metabolism Disorder, Glucose	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, powder, for solution		1 mg/5ml
Powder, for solution	Parenteral	1 MG

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
isoelectric point	6.7	Rubin BY, Anderson SL, Sullivan SA, Williamson BD, Carswell EA, Old LJ. Purification and characterization of a human tumor necrosis factor from the LuKII cell line. Proc Natl Acad Sci USA. 1985;82(19):6637-41.

Targets

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Details1. Tumor necrosis factor receptor superfamily member 1A

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Agonist

General Function: Tumor necrosis factor-activated receptor activity
Specific Function: Receptor for TNFSF2/TNF-alpha and homotrimeric TNFSF1/lymphotoxin-alpha. The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC...
Gene Name: TNFRSF1A
Uniprot ID: P19438
Uniprot Name: Tumor necrosis factor receptor superfamily member 1A
Molecular Weight: 50494.3 Da

References

Wajant H, Pfizenmaier K, Scheurich P: Tumor necrosis factor signaling. Cell Death Differ. 2003 Jan;10(1):45-65. doi: 10.1038/sj.cdd.4401189. [Article]

Details2. Tumor necrosis factor receptor superfamily member 1B

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Agonist

General Function: Ubiquitin protein ligase binding
Specific Function: Receptor with high affinity for TNFSF2/TNF-alpha and approximately 5-fold lower affinity for homotrimeric TNFSF1/lymphotoxin-alpha. The TRAF1/TRAF2 complex recruits the apoptotic suppressors BIRC2 ...
Gene Name: TNFRSF1B
Uniprot ID: P20333
Uniprot Name: Tumor necrosis factor receptor superfamily member 1B
Molecular Weight: 48290.85 Da

References

Wajant H, Pfizenmaier K, Scheurich P: Tumor necrosis factor signaling. Cell Death Differ. 2003 Jan;10(1):45-65. doi: 10.1038/sj.cdd.4401189. [Article]

Drug created at October 17, 2016 21:25 / Updated at August 22, 2021 03:36

Tasonermin

Identification

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Targets

References

References