Identification
- Summary
Tagraxofusp is a CD123-directed cytotoxin used to treat plasmacytoid dendritic cell neoplasm.
- Brand Names
- Elzonris
- Generic Name
- Tagraxofusp
- DrugBank Accession Number
- DB14731
- Background
Tagraxofusp is an IL-3 conjugated truncated diphtheria toxin.4 It is composed by the catalytic and translocation domains of diphtheria toxin fused via Met-His linker to a full-length human IL-3.6,7 Tagraxofusp was developed by Stemline Therapeutics Inc and FDA approved on December 21, 2018, as the first therapy for blastic plasmacytoid dendritic cell neoplasm.3 This drug achieved approval after being designated with the title of breakthrough therapy, priority review, and orphan drug status.2 Tagraxofusp has been designated as an orphan drug in the EU since November 2015.7
- Type
- Biotech
- Groups
- Approved, Investigational
- Biologic Classification
- Protein Based Therapies
Fusion proteins - Protein Structure
- Protein Chemical Formula
- C2553 H4026 N692 O798 S16
- Protein Average Weight
- Not Available
- Sequences
>>tagraxofusp<<< MGADDVVDSSKSFVMENFSSYHGTKPGYVDSIQKGIQKPKSGTQGNYDDDWKGFYSTDNK YDAAGYSVDNENPLSGKAGGVVKVTYPGLTKVLALKVDNAETIKKELGLSLTEPLMEQVG TEEFIKRFGDGASRVVLSLPFAEGSSSVEYINNWEQAKALSVELEINFETRGKRGQDAMY EYMAQACAGNRVRRSVGSSLSCINLDWDVIRDKTKTKIESLKEHGPIKNKMSESPNKTVS EEKAKQYLEEFHQTALEHPELSELKTVTGTNPVFAGANYAAWAVNVAQVIDSETADNLEK TTAALSILPGIGSVMGIADGAVHHNTEEIVAQSIALSSLMVAQAIPLVGELVDIGFAAYN FVESIINLFQVVHNSYNRPAYSPGHKTRPHMAPMTQTTSLKTSWVNCSNMIDEIITHLKQ PPLPLLDFNNLNGEDQDILMENNLRRPNLEAFNRAVKSLQNASAIESILKNLLPCLPLAT AAPTRHPIHIKDGDWNEFRRKLTFYLKTLENAQAQQTTLSLAIF
Download FASTA FormatReferences:
- WHO reports [Link]
- Synonyms
- Diphtheria toxin-il-3 fusion protein targeting IL-3 receptor
- Tagraxofusp
- tagraxofusp-erzs
- External IDs
- DT-3881L3
- DT388IL3
- Molecule 129
- Molecule-129
- SL-401
Pharmacology
- Indication
Tagraxofusp is indicated for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and pediatric patients over 2 years old. This treatment allows an alternative for the previous intense treatment which consisted of intensive chemotherapy followed by bone marrow transplantation.2
BPDCN is a rare hematologic malignancy derived from plasmacytoid dendritic cells. It is characterized by the significantly increased expression of cells expressing CD4/CD56/CD123 and other markers restricted to plasmacytoid dendritic cells and a lack of expression of lymphoid, natural killer or myeloid lineage-associated antigens.1 A key feature of the malignant cells is the overexpression of CD123, also known as interleukin-3 receptor, and the constant requirement of IL-3 for survival.6
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- Contraindications & Blackbox Warnings
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In vitro studies showed that BPDCN blasts are ultrasensitive to tagraxofusp by presenting IC50 values in the femtomolar scale.6 One of the main physiological changes of BPDCN is the presence of elevated interferon alpha and to produce an inflammatory response. In trials with tagraxofusp and following cell depletion, there was observed a significant reduction in the levels of interferon alpha and interleukin 6.5
In clinical trials, tagraxofusp reported complete remission and complete remission with a skin abnormality not indicative of active disease in 54% of the treated patients.2
- Mechanism of action
Tagraxofusp binds to cells expressing the IL-3 receptor and delivers in them the diphtheria toxin after binding. This is very useful as the malignant cells in BPDCN present a particularly high expression of IL-3 receptor (CD123+ pDC).5 To be more specific, tagraxofusp gets internalized to the IL-3 receptor-expressing cell allowing for diphtheria toxin translocation to the cytosol and followed by the binding to ADP-ribosylation elongation factor 2 which is a key factor for protein translation. Once the protein synthesis is inhibited, the cell goes under a process of apoptosis.4,6
As the apoptosis induction requires an active state of protein synthesis, tagraxofusp is not able to perform its apoptotic function in dormant cells.6
Target Actions Organism AInterleukin-3 receptor subunit alpha binderHumans AADP-ribosylation factor-like protein 2 binderHumans - Absorption
The reported Cmax in clinical trials was of around 23 ng/ml.6 After a 15 min infusion of a dose of 12 mcg/kg the registered AUC and Cmax was 231 mcg.h/L and 162 mcg/L respectively.Label
- Volume of distribution
In BPDCN patients, the reported volume of distribution is of 5.1 L.Label
- Protein binding
Tagraxofusp is not a substrate of p-glycoprotein and other efflux pump proteins associated with multidrug resistance.6
- Metabolism
For the metabolism, as tagraxofusp is a fusion protein, it is expected to get processed until small peptides and amino acids by the actions of proteases.
- Route of elimination
Tagraxofusp is eliminated as small peptides and amino acids. More studies need to be performed to confirm the main elimination route.
- Half-life
The reported half-life of tagraxofusp is of around 51 minutes.6
- Clearance
The clearance of tagraxofusp was reported to fit a mono-exponential model.6 The reported clearance rate is reported to be of 7.1 L/h.Label
- Adverse Effects
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There haven't been analysis observing the carcinogenic, mutagenic potential nor the effect on fertility. However, in studies performed in cynomolgus monkeys at an overdose rate of 1.6 times the recommended dose, it was observed severe kidney tubular degeneration. Similar studies at the recommended dose reported the presence of degeneration and necrosis of choroid plexus in the brain were. This effect seems to be progressive even 3 weeks after therapy withdrawal.Label
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareDarbepoetin alfa The risk or severity of Thrombosis can be increased when Darbepoetin alfa is combined with Tagraxofusp. Erythropoietin The risk or severity of Thrombosis can be increased when Erythropoietin is combined with Tagraxofusp. Methoxy polyethylene glycol-epoetin beta The risk or severity of Thrombosis can be increased when Methoxy polyethylene glycol-epoetin beta is combined with Tagraxofusp. Peginesatide The risk or severity of Thrombosis can be increased when Peginesatide is combined with Tagraxofusp. 
Identify potential medication risksEasily compare up to 40 drugs with our drug interaction checker.Get severity rating, description, and management advice.Learn more - Food Interactions
- No interactions found.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Elzonris Injection, solution, concentrate 1 mg/ml Intravenous Stemline Therapeutics B.V. 2021-01-28 Not applicable EU 
Elzonris Injection, solution 1000 ug/1mL Intravenous Stemline Therapeutics, Inc. 2019-01-18 Not applicable US 
Categories
- ATC Codes
- L01XX67 — Tagraxofusp
- 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
- Humans and other mammals
Chemical Identifiers
- UNII
- 8ZHS5657EH
- CAS number
- 2055491-00-2
References
- General References
- Kharfan-Dabaja MA, Lazarus HM, Nishihori T, Mahfouz RA, Hamadani M: Diagnostic and therapeutic advances in blastic plasmacytoid dendritic cell neoplasm: a focus on hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2013 Jul;19(7):1006-12. doi: 10.1016/j.bbmt.2013.01.027. Epub 2013 Feb 5. [Article]
- FDA news [Link]
- FDA Approved Drug Products: Apadaz (benzhydrocodone and acetaminophen) tablets [Link]
- Oncology nursing news [Link]
- Stemline therapeutics news [Link]
- Blood journal [Link]
- NHS reports [Link]
- External Links
- 2109054
- Wikipedia
- Tagraxofusp
- FDA label
- Download (455 KB)
Clinical Trials
- Clinical Trials
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution Intravenous 1000 ug/1mL Injection, solution, concentrate Intravenous 1 mg/ml - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Binder
- General Function
- Interleukin-3 receptor activity
- Specific Function
- This is a receptor for interleukin-3.
- Gene Name
- IL3RA
- Uniprot ID
- P26951
- Uniprot Name
- Interleukin-3 receptor subunit alpha
- Molecular Weight
- 43329.585 Da
References
- Stemline therapeutics news [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Binder
- General Function
- Small GTP-binding protein which cycles between an inactive GDP-bound and an active GTP-bound form, and the rate of cycling is regulated by guanine nucleotide exchange factors (GEF) and GTPase-activating proteins (GAP). GTP-binding protein that does not act as an allosteric activator of the cholera toxin catalytic subunit. Regulates formation of new microtubules and centrosome integrity. Prevents the TBCD-induced microtubule destruction. Participates in association with TBCD, in the disassembly of the apical junction complexes. Antagonizes the effect of TBCD on epithelial cell detachment and tight and adherens junctions disassembly. Together with ARL2, plays a role in the nuclear translocation, retention and transcriptional activity of STAT3. Component of a regulated secretory pathway involved in Ca(2+)-dependent release of acetylcholine. Required for normal progress through the cell cycle.
- Specific Function
- Gtp binding
- Gene Name
- ARL2
- Uniprot ID
- P36404
- Uniprot Name
- ADP-ribosylation factor-like protein 2
- Molecular Weight
- 20877.765 Da
References
Drug created at December 21, 2018 18:08 / Updated at August 17, 2021 04:17