Aldesleukin

Identification

Summary

Aldesleukin is a recombinant analog of interleukin-2 used to induce an adaptive immune response in the treatment of renal cell carcinoma.

Brand Names
Proleukin
Generic Name
Aldesleukin
DrugBank Accession Number
DB00041
Background

Aldesleukin, a lymphokine, is produced by recombinant DNA technology using a genetically engineered E. coli strain containing an analog of the human interleukin-2 gene. Genetic engineering techniques were used to modify the human IL-2 gene, and the resulting expression clone encodes a modified human interleukin-2. This recombinant form differs from native interleukin-2 in the following ways: a) Aldesleukin is not glycosylated because it is derived from E. coli; b) the molecule has no N-terminal alanine; the codon for this amino acid was deleted during the genetic engineering procedure; c) the molecule has serine substituted for cysteine at amino acid position 125.

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Interleukin-based products
Protein Structure
Db00041
Protein Chemical Formula
C690H1115N177O202S6
Protein Average Weight
15314.8 Da
Sequences
>Aldesleukin (CS373812.1 Sequence 2 from Patent EP1688146)
MPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLE
EELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR
WITFSQSIISTLT
References:
  1. NCBI: CS373812.1 [Link]
Download FASTA Format
Synonyms
  • 125-L-serine-2-133-interleukin 2 (human reduced)
  • Aldesleukin
  • Aldesleukina
  • ILT-101
  • ILT101
  • Interleukin-2 aldesleukin
  • Interleukin-2(2-133),125-ser
  • Recombinant human interleukin-2
  • Recombinant interleukin-2 human

Pharmacology

Indication

For treatment of adults with metastatic renal cell carcinoma.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Used to treat renal cell carcinoma, Aldesleukin induces the enhancement of lymphocyte mitogenesis and stimulation of long-term growth of human interleukin-2 dependent cell lines, the enhancement of lymphocyte cytotoxicity, the induction of killer cell (lymphokine-activated (LAK) and natural (NK)) activity; and the induction of interferon-gamma production. IL-2 is normally produced by the body, secreted by T cells, and stimulates growth and differentiation of T cell response. It can be used in immunotherapy to treat cancer. It enhances the ability of the immune system to kill tumor cells and may interfere with blood flow to the tumor.

Mechanism of action

Aldesleukin binds to the IL-2 receptor which leads to heterodimerization of the cytoplasmic domains of the IL-2R beta and gamma(c) chains, activation of the tyrosine kinase Jak3, and phosphorylation of tyrosine residues on the IL-2R beta chain. These events led to the creation of an activated receptor complex, to which various cytoplasmic signaling molecules are recruited and become substrates for regulatory enzymes (especially tyrosine kinases) that are associated with the receptor. These events stimulate growth and differentiation of T cells.

TargetActionsOrganism
AInterleukin-2 receptor subunit beta
agonist
modulator
Humans
AInterleukin-2 receptor subunit alpha
agonist
modulator
Humans
ACytokine receptor common subunit gamma
agonist
Humans
Absorption

Not Available

Volume of distribution

0.18 l/kg

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

The pharmacokinetic profile of Proleukin is characterized by high plasma concentrations following a short IV infusion, rapid distribution into the extravascular space and elimination from the body by metabolism in the kidneys with little or no bioactive protein excreted in the urine. Following the initial rapid organ distribution, the primary route of clearance of circulating proleukin is the kidney. Greater than 80% of the amount of Proleukin distributed to plasma, cleared from the circulation and presented to the kidney is metabolized to amino acids in the cells lining the proximal convoluted tubules.

Half-life

13 min-85 min

Clearance

Not Available

Adverse Effects
Adverseeffects
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Toxicity

Not Available

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
AbacavirAldesleukin may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbaloparatideThe therapeutic efficacy of Abaloparatide can be decreased when used in combination with Aldesleukin.
AbataceptThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Aldesleukin.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Aldesleukin.
AcalabrutinibThe metabolism of Acalabrutinib can be decreased when combined with Aldesleukin.
AcebutololThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Acebutolol.
AceclofenacAceclofenac may decrease the excretion rate of Aldesleukin which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Aldesleukin which could result in a higher serum level.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Aldesleukin.
Interactions
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Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ProleukinPowder, for solution22000000 unit / vialIntravenousSterimax Inc1995-12-31Not applicableCanada flag
ProleukinInjection1.1 mg/1mLIntravenousNovartis1992-05-062017-01-01US flag
ProleukinInjection, powder, lyophilized, for solution1.1 mg/1mLIntravenousClinigen Group PLC1992-05-05Not applicableUS flag
ProleukinInjection1.1 mg/1mLIntravenousPhysicians Total Care, Inc.2006-05-222011-06-30US flag
ProleukinInjection, powder, lyophilized, for solution1.1 mg/1mLIntravenousPrometheus Laboratories Inc.1992-05-05Not applicableUS flag

Categories

ATC Codes
L03AC01 — Aldesleukin
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
M89N0Q7EQR
CAS number
110942-02-4

References

Synthesis Reference

Hans-Ake Fabricius, Roland Stahn, "Serum-free and mitogen-free T-cell growth factor and process for making same." U.S. Patent US4464355, issued May, 1971.

US4464355
General References
  1. PROLEUKIN® (aldesleukin) FDA label [Link]
UniProt
P60569
Genbank
M11144
PubChem Substance
46508054
RxNav
70223
ChEMBL
CHEMBL1201438
Therapeutic Targets Database
DAP001099
PharmGKB
PA448081
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Interleukin_2

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentAcute Myeloid Leukemia (AML)1
4CompletedTreatmentMetastatic Melanoma / Metastatic Renal Cell Carcinoma ( mRCC)1
4CompletedTreatmentRenal Cancers1
4TerminatedOtherMetastatic Melanoma1
4TerminatedTreatmentLiver Diseases / Transplantations1
4TerminatedTreatmentMetastatic Melanoma1
3Active Not RecruitingTreatmentLocalized Resectable Neuroblastoma / Localized Unresectable Neuroblastoma / Recurrent Neuroblastoma / Regional Neuroblastoma / Stage 4 Neuroblastoma / Stage 4S Neuroblastoma1
3CompletedTreatmentAdult Acute Basophilic Leukemia / Adult Acute Eosinophilic Leukemia / Adult Acute Erythroid Leukemia (M6) / Adult Acute Megakaryoblastic Leukemia (M7) / Adult Acute Minimally Differentiated Myeloid Leukemia (M0) / Adult Acute Monoblastic Leukemia (M5a) / Adult Acute Monoblastic Leukemia and Acute Monocytic Leukemia (M5) / Adult Acute Monocytic Leukemia (M5b) / Adult Acute Myeloblastic Leukemia With Maturation (M2) / Adult Acute Myeloblastic Leukemia Without Maturation (M1) / Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities / Adult Acute Myeloid Leukemia With Del(5q) / Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) / Adult Acute Myeloid Leukemia With T(16;16)(p13;q22) / Adult Acute Myeloid Leukemia With T(8;21)(q22;q22) / Adult Acute Myelomonocytic Leukemia (M4) / Adult Erythroleukemia (M6a) / Adult Pure Erythroid Leukemia (M6b) / Childhood Acute Basophilic Leukemia / Childhood Acute Eosinophilic Leukemia / Childhood Acute Erythroleukemia (M6) / Childhood Acute Megakaryocytic Leukemia (M7) / Childhood Acute Minimally Differentiated Myeloid Leukemia (M0) / Childhood Acute Monoblastic Leukemia (M5a) / Childhood Acute Monoblastic Leukemia and Acute Monocytic Leukemia (M5) / Childhood Acute Monocytic Leukemia (M5b) / Childhood Acute Myeloblastic Leukemia With Maturation (M2) / Childhood Acute Myeloblastic Leukemia Without Maturation (M1) / Childhood Acute Myelomonocytic Leukemia (M4) / Childhood Myelodysplastic Syndromes / De Novo Myelodysplastic Syndromes / Untreated Adult Acute Myeloid Leukemia / Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies1
3CompletedTreatmentBreast Cancer1
3CompletedTreatmentCancer of the Skin / Malignant Melanoma of Skin1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Bayer Healthcare
  • Chiron Corp.
  • Novartis AG
  • Physicians Total Care Inc.
  • Prometheus Laboratories Inc.
Dosage Forms
FormRouteStrength
InjectionIntravenous1.1 mg/1mL
Injection, powder, for solutionParenteral; Subcutaneous18000.000 UI/ML
Injection, powder, lyophilized, for solutionIntravenous1.1 mg/1mL
Powder, for solutionIntravenous22000000 unit / vial
Injection, powder, for solutionParenteral
Injection, powder, lyophilized, for solutionIntravenous
Prices
Unit descriptionCostUnit
Proleukin 22 million unit vial1092.34USD each
Proleukin 22000000 unit Solution Vial976.66USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Liquid
Experimental Properties
PropertyValueSource
hydrophobicity-0.192Not Available
isoelectric point7.31Not Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
Modulator
General Function
Interleukin-2 receptor activity
Specific Function
Receptor for interleukin-2. This beta subunit is involved in receptor mediated endocytosis and transduces the mitogenic signals of IL2.
Gene Name
IL2RB
Uniprot ID
P14784
Uniprot Name
Interleukin-2 receptor subunit beta
Molecular Weight
61116.59 Da
References
  1. Stauber DJ, Debler EW, Horton PA, Smith KA, Wilson IA: Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor. Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2788-93. Epub 2006 Feb 13. [Article]
  2. Steppan S, Eckart MR, Bajsarowicz K, Sternberg LR, Greve JM, Cassell DJ: Reduced secondary cytokine induction by BAY 50-4798, a high-affinity receptor-specific interleukin-2 analog. J Interferon Cytokine Res. 2006 Mar;26(3):171-8. [Article]
  3. Cornish GH, Sinclair LV, Cantrell DA: Differential regulation of T-cell growth by IL-2 and IL-15. Blood. 2006 Jul 15;108(2):600-8. Epub 2006 Mar 28. [Article]
  4. Lee KD, Chen HW, Chen CC, Shih YC, Liu HK, Cheng ML: Construction and characterization of a novel fusion protein consisting of anti-CD3 antibody fused to recombinant interleukin-2. Oncol Rep. 2006 May;15(5):1211-6. [Article]
  5. Maclennan C, Hutchinson P, Holdsworth S, Bardin PG, Freezer NJ: Airway inflammation in asymptomatic children with episodic wheeze. Pediatr Pulmonol. 2006 Jun;41(6):577-83. [Article]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
Modulator
General Function
Interleukin-2 receptor activity
Specific Function
Receptor for interleukin-2. The receptor is involved in the regulation of immune tolerance by controlling regulatory T cells (TREGs) activity. TREGs suppress the activation and expansion of autorea...
Gene Name
IL2RA
Uniprot ID
P01589
Uniprot Name
Interleukin-2 receptor subunit alpha
Molecular Weight
30818.915 Da
References
  1. Waldmann TA: Anti-Tac (daclizumab, Zenapax) in the treatment of leukemia, autoimmune diseases, and in the prevention of allograft rejection: a 25-year personal odyssey. J Clin Immunol. 2007 Jan;27(1):1-18. Epub 2007 Jan 11. [Article]
  2. Recchia F, Cesta A, Rea S: Low dose interleukin-2 and 13-cis-retinoic acid as maintenance therapy in patients with solid tumors responsive to chemotherapy. J Exp Clin Cancer Res. 2003 Dec;22(4 Suppl):135-43. [Article]
  3. Waldmann TA: Daclizumab (anti-Tac, Zenapax) in the treatment of leukemia/lymphoma. Oncogene. 2007 May 28;26(25):3699-703. [Article]
  4. Vlad G, Ho EK, Vasilescu ER, Fan J, Liu Z, Cai JW, Jin Z, Burke E, Deng M, Cadeiras M, Cortesini R, Itescu S, Marboe C, Mancini D, Suciu-Foca N: Anti-CD25 treatment and FOXP3-positive regulatory T cells in heart transplantation. Transpl Immunol. 2007 Jul;18(1):13-21. Epub 2007 Apr 2. [Article]
  5. Liu BY, Zhu P, Luo HB, Fu N: [Screening of short peptides binding to cell surface interleukin-2 receptor alpha chain]. Nan Fang Yi Ke Da Xue Xue Bao. 2006 Jul;26(7):971-4. [Article]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  7. Ouyang Y, Kaminski NE: Phospholipase A2 inhibitors p-bromophenacyl bromide and arachidonyl trifluoromethyl ketone suppressed interleukin-2 (IL-2) expression in murine primary splenocytes. Arch Toxicol. 1999 Feb;73(1):1-6. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Interleukin-2 binding
Specific Function
Common subunit for the receptors for a variety of interleukins.
Gene Name
IL2RG
Uniprot ID
P31785
Uniprot Name
Cytokine receptor common subunit gamma
Molecular Weight
42286.68 Da
References
  1. Stauber DJ, Debler EW, Horton PA, Smith KA, Wilson IA: Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor. Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2788-93. Epub 2006 Feb 13. [Article]
  2. Shibata F, Toma T, Wada T, Inoue M, Tone Y, Ohta K, Kasahara Y, Sano F, Kimura M, Ikeno M, Koizumi S, Yachie A: Skin infiltration of CD56(bright) CD16(-) natural killer cells in a case of X-SCID with Omenn syndrome-like manifestations. Eur J Haematol. 2007 Jul;79(1):81-5. [Article]
  3. Fonseca SG, Reis MM, Coelho V, Nogueira LG, Monteiro SM, Mairena EC, Bacal F, Bocchi E, Guilherme L, Zheng XX, Liew FY, Higuchi ML, Kalil J, Cunha-Neto E: Locally produced survival cytokines IL-15 and IL-7 may be associated to the predominance of CD8+ T cells at heart lesions of human chronic Chagas disease cardiomyopathy. Scand J Immunol. 2007 Aug-Sep;66(2-3):362-71. [Article]
  4. Blank RB, Lamb EW, Tocheva AS, Crow ET, Lim KC, McKerrow JH, Davies SJ: The common gamma chain cytokines interleukin (IL)-2 and IL-7 indirectly modulate blood fluke development via effects on CD4+ T cells. J Infect Dis. 2006 Dec 1;194(11):1609-16. Epub 2006 Oct 23. [Article]
  5. Smyth CM, Ginn SL, Deakin CT, Logan GJ, Alexander IE: Limiting {gamma}c expression differentially affects signaling via the interleukin (IL)-7 and IL-15 receptors. Blood. 2007 Jul 1;110(1):91-8. Epub 2007 Mar 15. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Prostaglandin-endoperoxide synthase activity
Specific Function
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and...
Gene Name
PTGS2
Uniprot ID
P35354
Uniprot Name
Prostaglandin G/H synthase 2
Molecular Weight
68995.625 Da
References
  1. Pyeon D, Diaz FJ, Splitter GA: Prostaglandin E(2) increases bovine leukemia virus tax and pol mRNA levels via cyclooxygenase 2: regulation by interleukin-2, interleukin-10, and bovine leukemia virus. J Virol. 2000 Jun;74(12):5740-5. [Article]
  2. Hamada T, Tsuchihashi S, Avanesyan A, Duarte S, Moore C, Busuttil RW, Coito AJ: Cyclooxygenase-2 deficiency enhances Th2 immune responses and impairs neutrophil recruitment in hepatic ischemia/reperfusion injury. J Immunol. 2008 Feb 1;180(3):1843-53. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Phospholipase a2 activity
Specific Function
Selectively hydrolyzes arachidonyl phospholipids in the sn-2 position releasing arachidonic acid. Together with its lysophospholipid activity, it is implicated in the initiation of the inflammatory...
Gene Name
PLA2G4A
Uniprot ID
P47712
Uniprot Name
Cytosolic phospholipase A2
Molecular Weight
85238.2 Da
References
  1. Wolbink GJ, Schalkwijk C, Baars JW, Wagstaff J, van den Bosch H, Hack CE: Therapy with interleukin-2 induces the systemic release of phospholipase-A2. Cancer Immunol Immunother. 1995 Nov;41(5):287-92. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Elkahwaji J, Robin MA, Berson A, Tinel M, Letteron P, Labbe G, Beaune P, Elias D, Rougier P, Escudier B, Duvillard P, Pessayre D: Decrease in hepatic cytochrome P450 after interleukin-2 immunotherapy. Biochem Pharmacol. 1999 Apr 15;57(8):951-4. [Article]
  2. Sunman JA, Hawke RL, LeCluyse EL, Kashuba AD: Kupffer cell-mediated IL-2 suppression of CYP3A activity in human hepatocytes. Drug Metab Dispos. 2004 Mar;32(3):359-63. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Xanthine oxidase activity
Specific Function
Key enzyme in purine degradation. Catalyzes the oxidation of hypoxanthine to xanthine. Catalyzes the oxidation of xanthine to uric acid. Contributes to the generation of reactive oxygen species. Ha...
Gene Name
XDH
Uniprot ID
P47989
Uniprot Name
Xanthine dehydrogenase/oxidase
Molecular Weight
146422.99 Da
References
  1. Faggioni R, Allavena P, Cantoni L, Carelli M, Demitri MT, Delgado R, Gatti S, Gnocchi P, Isetta AM, Paganin C, et al.: Mechanisms of interleukin-2-induced hydrothoraxy in mice: protective effect of endotoxin tolerance and dexamethasone and possible role of reactive oxygen intermediates. J Immunother Emphasis Tumor Immunol. 1994 Apr;15(3):194-201. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
References
  1. Elkahwaji J, Robin MA, Berson A, Tinel M, Letteron P, Labbe G, Beaune P, Elias D, Rougier P, Escudier B, Duvillard P, Pessayre D: Decrease in hepatic cytochrome P450 after interleukin-2 immunotherapy. Biochem Pharmacol. 1999 Apr 15;57(8):951-4. [Article]

Drug created on June 13, 2005 13:24 / Updated on September 19, 2021 19:53