Identification

Name
Tasonermin
Accession Number
DB11626
Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Other protein based therapies
Description

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.

Protein structure
Db11626
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
  • Tumor necrosis factor, soluble form, nonglycosylated
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
BeromunInjection, powder, for solution1 mg/5mlBoehringer Ingelheim1999-04-13Not applicableEu
Categories
UNII
23CA79S88F
CAS number
94948-59-1

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.

Associated Conditions
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].

TargetActionsOrganism
ATumor necrosis factor receptor superfamily member 1A
agonist
Human
UTumor necrosis factor receptor superfamily member 1B
agonist
Human
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.

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.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. 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. [PubMed:7542214]
  2. 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. [PubMed:12655295]
  3. 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. [PubMed:19118493]
  4. 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. [PubMed:21275341]
  5. 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]
  6. EMA: Tasonermin Scientific Discussion [Link]
External Links
Wikipedia
Tasonermin
ATC Codes
L03AX11 — Tasonermin
FDA label
Download (193 KB)
MSDS
Download (31.8 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1WithdrawnTreatmentMalignant Lymphomas / Tumors, Solid1
Not AvailableCompletedNot AvailableGlucose Metabolism Disorders / Inflammatory Reaction1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, for solution1 mg/5ml
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
isoelectric point6.7Rubin 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.

Taxonomy

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

Targets

Kind
Protein
Organism
Human
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
  1. 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. [PubMed:12655295]
Kind
Protein
Organism
Human
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
  1. 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. [PubMed:12655295]

Drug created on October 17, 2016 15:25 / Updated on August 02, 2018 06:27