Identification

Name
Dinutuximab
Accession Number
DB09077
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

Dinutuximab is an IgG1 monoclonal human/mouse chimeric antibody against GD2, a disialoganglioside expressed on tumors of neuroectodermal origin, including human neuroblastoma and melanoma, with highly restricted expression on normal tissues. It is composed of the variable heavy- and light-chain regions of the murine anti-GD2 mAb 14.18 and the constant regions of human IgG1 heavy-chain and kappa light-chain. By binding to GD2, dinutiximab induces antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity of tumor cells thereby leading to apoptosis and inhibiting proliferation of the tumour. It is indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy. Despite a high clinical response seen after first-line treatment, the complete eradication of neuroblastoma is rarely achieved and the majority of patients with advanced disease suffer a relapse. Current strategies for treatment include immunotherapy with drugs such as dinutuximab to target surviving neuroblastoma cells and to prevent relapse.

Protein chemical formula
C6422H9982N1722O2008S48
Protein average weight
145000.0 Da
Sequences
Not Available
Synonyms
  • Dinutuximab beta
  • Monoclonal antibody ch14.18
External IDs
APN-311 / APN311 / ch14.18 / ch14.18-UTC
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
UnituxinInjection3.5 mg/1mLIntravenousUnited Therapeutics2015-03-10Not applicableUs
Categories
UNII
7SQY4ZUD30
CAS number
1363687-32-4

Pharmacology

Indication

Dinutuximab is indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy. Despite a high clinical response seen after first-line treatment, the complete eradication of neuroblastoma is rarely achieved and the majority of patients with advanced disease suffer a relapse. Current strategies for treatment include immunotherapy with drugs such as dinutuximab to target surviving neuroblastoma cells and to prevent relapse.

Associated Conditions
Pharmacodynamics

In vitro dinutuximab binds to neuroblastoma tumour cells and mediates the lysis of tumour cells via cell-mediated and complement-mediated cytotoxicity.

Mechanism of action

Dinutuximab is an IgG1 monoclonal human/mouse chimeric antibody against GD2, a disialoganglioside expressed on tumors of neuroectodermal origin, including human neuroblastoma and melanoma, with highly restricted expression on normal tissues. It is composed of the variable heavy- and light-chain regions of the murine anti-GD2 mAb 14.18 and the constant regions of human IgG1 heavy-chain and kappa light-chain. By binding to GD2, dinutiximab induces antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity of tumor cells thereby leading to apoptosis and inhibiting proliferation of the tumour.

TargetActionsOrganism
AGanglioside GD2
inhibitor
Human
Absorption
Not Available
Volume of distribution

The mean volume of distribution at steady state (Vdss) is 5.4 L

Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life

The terminal half-life is 10 days

Clearance

The clearance is 0.21 L/day and increases with body size

Toxicity

The most common (incidence 15 %) grade 3 or 4 treatment-related adverse events in dinutuximab compared with standard therapy recipients were neuropathic pain (52 vs. 6 %), fever without neutropenia (39 vs. 6 %), any in-fection (39 vs. 22 %), hypokalaemia (35 vs. 2 %), hypersensitivity reactions (25 vs. 1 %), hyponatraemia (23 vs. 4 %), elevation of alanine transferase levels (23 vs. 3 %) and hypotension (18 vs. 0 %). Based on its mechanism of action, dinutuximab may cause fetal harm when administered to a pregnant woman however, there are no studies in pregnant women and no reproductive studies in animals to inform the drug-associated risk. Non-clinical studies suggest that dinutuximab-induced neuropathic pain is mediated by binding of the antibody to the GD2 antigen located on the surface of peripheral nerve fibers and myelin and subsequent induction of cell- and complement-mediated cytotoxicity. In clinical trials, 114 (85%) patients treated in the dinutuximab/RA group experienced pain despite preĀ­-treatment with analgesics including morphine sulfate infusion. Severe (Grade 3) pain occurred in 68 (51%) patients in the dinutuximab/RA group compared to 5 (5%) patients in the RA group. Pain typically occurred during the dinutuximab infusion and was most commonly reported as abdominal pain, generalized pain, extremity pain, back pain, neuralgia, musculoskeletal chest pain, and arthralgia.

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

Interactions

Drug Interactions
DrugInteraction
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Dinutuximab.
AcebutololThe risk or severity of adverse effects can be increased when Acebutolol is combined with Dinutuximab.
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Dinutuximab.
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Dinutuximab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Dinutuximab.
AlclometasoneThe risk or severity of adverse effects can be increased when Dinutuximab is combined with Alclometasone.
AldesleukinThe risk or severity of adverse effects can be increased when Dinutuximab is combined with Aldesleukin.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Dinutuximab.
AliskirenThe risk or severity of adverse effects can be increased when Aliskiren is combined with Dinutuximab.
AmcinonideThe risk or severity of adverse effects can be increased when Dinutuximab is combined with Amcinonide.
Food Interactions
Not Available

References

General References
  1. Dhillon S: Dinutuximab: first global approval. Drugs. 2015 May;75(8):923-7. doi: 10.1007/s40265-015-0399-5. [PubMed:25940913]
  2. Ahmed M, Cheung NK: Engineering anti-GD2 monoclonal antibodies for cancer immunotherapy. FEBS Lett. 2014 Jan 21;588(2):288-97. doi: 10.1016/j.febslet.2013.11.030. Epub 2013 Dec 1. [PubMed:24295643]
  3. Barker E, Mueller BM, Handgretinger R, Herter M, Yu AL, Reisfeld RA: Effect of a chimeric anti-ganglioside GD2 antibody on cell-mediated lysis of human neuroblastoma cells. Cancer Res. 1991 Jan 1;51(1):144-9. [PubMed:1988079]
  4. Aixinjueluo W, Furukawa K, Zhang Q, Hamamura K, Tokuda N, Yoshida S, Ueda R, Furukawa K: Mechanisms for the apoptosis of small cell lung cancer cells induced by anti-GD2 monoclonal antibodies: roles of anoikis. J Biol Chem. 2005 Aug 19;280(33):29828-36. Epub 2005 May 26. [PubMed:15923178]
External Links
KEGG Drug
D10559
PubChem Substance
347910402
ChEMBL
CHEMBL3137342
Drugs.com
Drugs.com Drug Page
Wikipedia
Dinutuximab
ATC Codes
L01XC16 — Dinutuximab
FDA label
Download (446 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentDisseminated Neuroblastoma / Recurrent Neuroblastoma / Regional Neuroblastoma1
1Not Yet RecruitingTreatmentNeuroblastomas1
1RecruitingTreatmentNeuroblastomas1
1SuspendedTreatmentRecurrent Neuroblastoma / Refractory Neuroblastoma / Stage 4 Neuroblastoma1
1, 2CompletedTreatmentNeuroblastomas1
2Active Not RecruitingTreatmentEffects of Immunotherapy / Neoplasm, Residual / Neuroblastomas1
2Active Not RecruitingTreatmentGanglioneuroblastoma / Recurrent Neuroblastoma1
2RecruitingTreatmentNeuroblastomas2
2SuspendedTreatmentMetastatic Bone Sarcomas / Metastatic Malignant Neoplasm in the Lung / Recurrent Osteosarcoma1
2TerminatedTreatmentNeuroblastomas1
2Unknown StatusTreatmentRecurrent Neuroblastoma1
2, 3RecruitingTreatmentLung Cancer Small Cell Lung Cancer (SCLC)1
3CompletedTreatmentDisseminated Neuroblastoma / Localized Resectable Neuroblastoma / Localized Unresectable Neuroblastoma / Regional Neuroblastoma / Stage 4 Neuroblastoma / Stage 4S Neuroblastoma1
3CompletedTreatmentLocalized Resectable Neuroblastoma / Localized Unresectable Neuroblastoma / Recurrent Neuroblastoma / Regional Neuroblastoma / Stage 4 Neuroblastoma / Stage 4S Neuroblastoma1
3RecruitingTreatmentChildhood Ganglioneuroblastoma / Childhood Neuroblastoma / INRG Stage L2 / INRG Stage M / INRG Stage MS / NMYC Gene Amplification / Recurrent Neuroblastoma1
3Unknown StatusTreatmentNeuroblastomas1
Not AvailableTerminatedNot AvailableNeuroblastomas1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
InjectionIntravenous3.5 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US20140170155No2014-02-182038-02-18Us

Properties

State
Solid
Experimental Properties
Not Available

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
Small molecule
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
References
  1. Barker E, Mueller BM, Handgretinger R, Herter M, Yu AL, Reisfeld RA: Effect of a chimeric anti-ganglioside GD2 antibody on cell-mediated lysis of human neuroblastoma cells. Cancer Res. 1991 Jan 1;51(1):144-9. [PubMed:1988079]

Drug created on June 18, 2015 11:47 / Updated on August 02, 2018 06:13