Identification

Summary

Tagraxofusp is a CD123-directed cytotoxin used to treat blastic plasmacytoid dendritic cell neoplasm.

Brand Names
Elzonris
Generic Name
Tagraxofusp
DrugBank Accession Number
DB14731
Background

Tagraxofusp is a CD123-directed cytotoxin. It is a fusion protein composed of a human interleukin-3 (IL-3) that is genetically fused to the catalytic and translocation domains of truncated diphtheria toxin (DT) produced in Escherichia coli.1,2,4 Tagraxofusp received its first global approval by the FDA on December 21, 2018 as the first FDA-approved treatment for blastic plasmacytoid dendritic cell neoplasm, which is a myeloid malignancy in the dendritic cell lineage.1 It was also approved by the European Commission on January 7, 2021.5

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
57695.0 Da (approximate)
Sequences
>Tagraxofusp sequence
MGADDVVDSSKSFVMENFSSYHGTKPGYVDSIQKGIQKPKSGTQGNYDDDWKGFYSTDNK
YDAAGYSVDNENPLSGKAGGVVKVTYPGLTKVLALKVDNAETIKKELGLSLTEPLMEQVG
TEEFIKRFGDGASRVVLSLPFAEGSSSVEYINNWEQAKALSVELEINFETRGKRGQDAMY
EYMAQACAGNRVRRSVGSSLSCINLDWDVIRDKTKTKIESLKEHGPIKNKMSESPNKTVS
EEKAKQYLEEFHQTALEHPELSELKTVTGTNPVFAGANYAAWAVNVAQVIDSETADNLEK
TTAALSILPGIGSVMGIADGAVHHNTEEIVAQSIALSSLMVAQAIPLVGELVDIGFAAYN
FVESIINLFQVVHNSYNRPAYSPGHKTRPHMAPMTQTTSLKTSWVNCSNMIDEIITHLKQ
PPLPLLDFNNLNGEDQDILMENNLRRPNLEAFNRAVKSLQNASAIESILKNLLPCLPLAT
AAPTRHPIHIKDGDWNEFRRKLTFYLKTLENAQAQQTTLSLAIF
References:
  1. KEGG DRUG: Tagraxofusp [Link]
Download FASTA Format
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 the US, it is approved for use in adults and pediatric patients over 2 years old.4 In Europe, it is only approved for use in adults.5

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Associated Conditions
Associated Therapies
Contraindications & Blackbox Warnings
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Pharmacodynamics

Tagraxofusp has potent antitumour activity against BPDCN cells in both in vitro and in vivo models.3 It is a cytotoxin that works to cause cell death in malignant cells that express CD123, which is a subunit of the interleukin 3 (IL-3) receptor. In vitro, tagraxofusp decreased cell proliferation and increased expression of apoptotic markers in BPDCN cell lines and in blasts from patients with BPDCN.1

Mechanism of action

Interleukin 3 (IL-3) is a cytokine and hematopoietic growth factor that promotes the differentiation of hematopoietic cells into various myeloid cells. It mediates its biological actions by binding to the IL-3 receptor, which is made up of two subunits: the alpha (α) subunit - also known as CD123 - is the site of ligand attachment and confers receptor specificity, while the beta (β) subunit, also known as CDw131 - plays a role in signal transduction, internalization of the ligand-receptor complexes, and activation of the Ras signalling pathway.2 The expression of the IL-3 receptor is prevalent in CD34+ hematopoietic cells as well as on granulocytes and monocyte precursors.1 CD123, the subunit of the IL-3 receptor, has also been implicated in the pathophysiology of BPDCN, as transformed plasmacytoid dendritic cells that overexpress CD123 are frequently observed.1,3

Tagraxofusp targets leukemic stem cells that express CD123.1 It is a fusion protein made up of diphtheria toxin (DT) and IL-3; therefore, it binds to the IL-3 receptor with high affinity. Upon binding to the IL-3 receptor on CD123-expressing cells, tagraxofusp is internalized via receptor-mediated endocytosis. The catalytic domain of DT is then cleaved and translocates from the endosome into the cytosol.2 The catalytic domain of DT irreversibly inhibits protein synthesis by inactivating elongation factor 2 (EF2),5 eventually inducing apoptosis.4,5

TargetActionsOrganism
AInterleukin-3 receptor subunit alpha
ligand
Humans
Absorption

Following administration of tagraxofusp 12 mcg/kg via 15-minute infusion in patients with BPDCN, the mean (SD) area under the plasma drug concentration over time curve (AUC) was 231 (123) hr x mcg/L and maximum plasma concentration (Cmax) was 162 (58.1) mcg/L.4

Volume of distribution

Following administration of tagraxofusp 12 mcg/kg via 15-minute infusion in patients with BPDCN, the mean (SD) volume of distribution of tagraxofusp was 5.1 (1.9) L.4

Protein binding

No information available.

Metabolism

Tagraxofusp is expected to be degraded into peptides and its constituent amino acids through proteolysis, with no involvement of CYP or transporters.5

Route of elimination

No information available.

Half-life

The mean (SD) terminal half-life of tagraxofusp was 0.7 (0.3) hours in patients with BPDCN.4

Clearance

Mean clearance (SD) clearance was 7.1 (7.2) L/hr in patients with BPDCN.4

Adverse Effects
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Toxicity

There is limited information regarding acute toxicity and overdosage of tagraxofusp.

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
ArticaineThe risk or severity of methemoglobinemia can be increased when Tagraxofusp is combined with Articaine.
BenzocaineThe risk or severity of methemoglobinemia can be increased when Tagraxofusp is combined with Benzocaine.
Benzyl alcoholThe risk or severity of methemoglobinemia can be increased when Tagraxofusp is combined with Benzyl alcohol.
BupivacaineThe risk or severity of methemoglobinemia can be increased when Tagraxofusp is combined with Bupivacaine.
ButacaineThe risk or severity of methemoglobinemia can be increased when Tagraxofusp is combined with Butacaine.
ButambenThe risk or severity of methemoglobinemia can be increased when Tagraxofusp is combined with Butamben.
CapsaicinThe risk or severity of methemoglobinemia can be increased when Tagraxofusp is combined with Capsaicin.
ChloroprocaineThe risk or severity of methemoglobinemia can be increased when Tagraxofusp is combined with Chloroprocaine.
CinchocaineThe risk or severity of methemoglobinemia can be increased when Tagraxofusp is combined with Cinchocaine.
CocaineThe risk or severity of methemoglobinemia can be increased when Tagraxofusp is combined with Cocaine.
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Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ElzonrisInjection, solution, concentrate1 mg/mlIntravenousStemline Therapeutics B.V.2021-01-28Not applicableEU flag
ElzonrisInjection, solution1000 ug/1mLIntravenousStemline Therapeutics, Inc.2019-01-18Not applicableUS flag

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
  1. Jen EY, Gao X, Li L, Zhuang L, Simpson NE, Aryal B, Wang R, Przepiorka D, Shen YL, Leong R, Liu C, Sheth CM, Bowen S, Goldberg KB, Farrell AT, Blumenthal GM, Pazdur R: FDA Approval Summary: Tagraxofusp-erzs For Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm. Clin Cancer Res. 2020 Feb 1;26(3):532-536. doi: 10.1158/1078-0432.CCR-19-2329. Epub 2019 Sep 23. [Article]
  2. Alkharabsheh O, Frankel AE: Clinical Activity and Tolerability of SL-401 (Tagraxofusp): Recombinant Diphtheria Toxin and Interleukin-3 in Hematologic Malignancies. Biomedicines. 2019 Jan 5;7(1). pii: biomedicines7010006. doi: 10.3390/biomedicines7010006. [Article]
  3. Pemmaraju N, Lane AA, Sweet KL, Stein AS, Vasu S, Blum W, Rizzieri DA, Wang ES, Duvic M, Sloan JM, Spence S, Shemesh S, Brooks CL, Balser J, Bergstein I, Lancet JE, Kantarjian HM, Konopleva M: Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm. N Engl J Med. 2019 Apr 25;380(17):1628-1637. doi: 10.1056/NEJMoa1815105. [Article]
  4. FDA Approved Drug Products: ELZONRIS (tagraxofusp-erzs) injection, for intravenous use [Link]
  5. EMA Approved Drug Products: Elzonris (tagraxofusp) Intravenous Infusion [Link]
RxNav
2109054
Wikipedia
Tagraxofusp

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2Active Not RecruitingTreatmentBlastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)1
2Active Not RecruitingTreatmentChronic Myelomonocytic Leukemia / Myelofibrosis1
2Not Yet RecruitingTreatmentAcute Myeloid Leukemia1
2RecruitingTreatmentAcute Myeloid Leukemia1
2RecruitingTreatmentBlastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)1
1RecruitingTreatmentAcute Myeloid Leukemia / Acute Undifferentiated Leukemia (AUL) / All / B-Cell Lymphoma / BPDCN / Haematological Malignancies / Hodgkin's Lymphoma / Lymphoblastic Lymphoma / Mixed Phenotype Acute Leukemia (MPAL) / Myelodysplastic Syndromes (MDS) / T-cell type lymphoma1
1RecruitingTreatmentAcute Myeloid Leukemia / Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) / Myelodysplastic Syndromes (MDS)1
1RecruitingTreatmentAcute Myeloid Leukemia / Chronic Myelomonocytic Leukemia / Myelofibrosis1
1, 2CompletedTreatmentAcute Myeloid Leukemia / Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)1
1, 2CompletedTreatmentBlastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) / Leukemias / Myelodysplastic Syndromes (MDS)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionIntravenous1000 ug/1mL
Injection, solution, concentrateIntravenous1 mg/ml
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Ligand
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
  1. Alkharabsheh O, Frankel AE: Clinical Activity and Tolerability of SL-401 (Tagraxofusp): Recombinant Diphtheria Toxin and Interleukin-3 in Hematologic Malignancies. Biomedicines. 2019 Jan 5;7(1). pii: biomedicines7010006. doi: 10.3390/biomedicines7010006. [Article]
  2. FDA Approved Drug Products: ELZONRIS (tagraxofusp-erzs) injection, for intravenous use [Link]

Drug created at December 21, 2018 18:08 / Updated at December 01, 2022 11:28