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| Primary information |
|---|
| ID | 15600 |
| Therapeutic ID | Th1611 |
| Protein Name | Tagraxofusp |
| Sequence | >Th1611_Tagraxofusp
MGADDVVDSSKSFVMENFSSYHGTKPGYVDSIQKGIQKPKSGTQGNYDDDWKGFYSTDNKYDAAGYSVDNENPLSGKAGGVVKVTYPGLTKVLALKVDNAETIKKELGLSLTEPLMEQVGTEEFIKRFGDGASRVVLSLPFAEGSSSVEYINNWEQAKALSVELEINFETRGKRGQDAMYEYMAQACAGNRVRRSVGSSLSCINLDWDVIRDKTKTKIESLKEHGPIKNKMSESPNKTVSEEKAKQYLEEFHQTALEHPELSELKTVTGTNPVFAGANYAAWAVNVAQVIDSETADNLEKTTAALSILPGIGSVMGIADGAVHHNTEEIVAQSIALSSLMVAQAIPLVGELVDIGFAAYNFVESIINLFQVVHNSYNRPAYSPGHKTRPHMAPMTQTTSLKTSWVNCSNMIDEIITHLKQPPLPLLDFNNLNGEDQDILMENNLRRPNLEAFNRAVKSLQNASAIESILKNLLPCLPLATAAPTRHPIHIKDGDWNEFRRKLTFYLKTLENAQAQQTTLSLAIF
|
| Molecular Weight | NA |
| Chemical Formula | C2553 H4026 N692 O798 S16 |
| Isoelectric Point | NA |
| Hydrophobicity | NA |
| Melting point | NA |
| Half-life | The reported half-life of tagraxofusp is of around 51 minutes.[L4897] |
| Description | Tagraxofusp is an IL-3 conjugated truncated diphtheria toxin.[L4895] It is composed by the catalytic and translocation domains of diphtheria toxin fused via Met-His linker to a full-length human IL-3.[L4897, L4898] Tagraxofusp was developed by Stemline Therapeutics Inc and FDA approved on December 21, 2018, as the first therapy for blastic plasmacytoid dendritic cell neoplasm.[L4894] This drug achieved approval after being designated with the title of breakthrough therapy, priority review, and orphan drug status.[L4893] Tagraxofusp has been designated as an orphan drug in the EU since November 2015.[L4898] |
| Indication/Disease | 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.[L4893] 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.[A40274] 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.[L4897] |
| Pharmacodynamics | In vitro studies showed that BPDCN blasts are ultrasensitive to tagraxofusp by presenting IC50 values in the femtomolar scale.[L4897] 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.[L4896] 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.[L4893] |
| 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).[L4896] 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.[L4895, L4897] As the apoptosis induction requires an active state of protein synthesis, tagraxofusp is not able to perform its apoptotic function in dormant cells.[L4897] |
| Toxicity | 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.[FDA label] |
| 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. |
| Absorption | The reported Cmax in clinical trials was of around 23 ng/ml.[L4897] 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.[FDA label] |
| In BPDCN patients, the reported volume of distribution is of 5.1 L.[FDA label] |
| Clearance | The clearance of tagraxofusp was reported to fit a mono-exponential model.[L4897] The reported clearance rate is reported to be of 7.1 L/h.[FDA label] |
| Categories | Antineoplastic Agents |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | Interleukin-3 receptor subunit alpha,ADP-ribosylation factor-like protein 2 |
| Brand Name | Elzonris |
| Company | Stemline Therapeutics, Inc. |
| Brand Description | Stemline Therapeutics, Inc. |
| Prescribed For | Intravenous |
| Chemical Name | 1000 ug/1mL |
| Formulation | None. |
| Physical Appearance | capillary leak syndrome, high or low blood pressure, nausea, fatigue, swelling of extremities, fever, weight gain, constipation, vomiting, diarrhea, chills, headache, dizziness, decreased appetite, back pain, pain in extremities, shortness of breath, cough, nosebleed, sore throat or mouth pain, insomnia, anxiety, confusion, fast heart rate, itching, small red or purple spots on the skin, or blood in the urine. |
| Route of Administration | Elzonris is used to treat blastic plasmacytoid dendritic cell neoplasm, a rare blood and/or bone marrow cancer. Elzonris is for use in adults and children at least 2 years old. Elzonris may also be used for purposes not listed in this medication guide. |
| Recommended Dosage | ELZONRIS is a CD123-directed cytotoxin for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and in pediatric patients 2 years and older. |
| Contraindication | NA |
| Side Effects | NA |
| Useful Link 1 | Link |
| Useful Link 2 | Link |
| Remarks | NA |