Identification

Summary

Naxitamab is a GD2-targeted IgG1 monoclonal antibody for the treatment of high-risk relapsed/refractory neuroblastoma of the bone or bone marrow.

Brand Names
Danyelza
Generic Name
Naxitamab
DrugBank Accession Number
DB15965
Background

Naxitamab (humanized 3F8, hu3F8) is an IgG1 monoclonal antibody directed against the oncofetal differentiation antigen GD2 disialoganglioside.6,4 Normally expressed during fetal development and in mature neurons, pain fibers, and skin cells, GD2 constitutes a highly efficient target in the treatment of neuroblastoma - it is widely expressed across and within neuroblastomas (and other neuroectodermal tumors),5 and is rarely subject to antigen loss.4

The first anti-GD2-monoclonal IgG antibody to be approved by the FDA for the treatment of neuroblastoma was dinutuximab under the brand name Unituxin in 2015.2 One stark disadvantage of this therapy is the requirement for concurrent use of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA).7

Naxitamab-gqgk (Danyelza) was granted accelerated approval by the FDA in November 2020 for the treatment of high-risk relapsed/refractory neuroblastoma of the bone or bone marrow.6 This approval requires naxitamab to be co-administered only with GM-CSF, a factor known to enhance the granulocyte-mediated antibody-dependent cytotoxicity of anti-GD2 therapies,4 making the administration of naxitamab therapy markedly simpler than that of its predecessor.

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
Not Available
Protein Average Weight
144000.0 Da (non-glycosylated)
Sequences
Not Available
Synonyms
  • Anti-Gd2 igg3 monoclonal antibody 3F8 humanized
  • Anti-Gd2 monoclonal antibody 3F8 humanized
  • HU3F8
  • Humanized 3F8
  • Humanized anti-Gd2 monoclonal antibody 3F8
  • Humanized monoclonal antibody HU3F8-IGG1
  • Monoclonal antibody HU3F8
  • Naxitamab
  • naxitamab-gqgk

Pharmacology

Indication

Naxitamab-gqgk is indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), for the treatment of patients 1 year of age and older with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response, minor response, or stable disease to prior therapy.6

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

In targeting cell surface glycoproteins (GD2) that occur on the surface of neuroendocrine tumors, naxitamab directs the immune system towards these cancerous cells and induces the activation of both complement-dependent and antibody-dependent cytotoxicity.6

Naxitamab can cause serious infusion reactions - including hypotension, hypoxia, anaphylaxis, and cardiac arrest - that necessitate careful monitoring during therapy. All patients should be pre-medicated with intravenous corticosteroids (e.g. methylprednisolone) as well as an antihistamine, H2 receptor antagonist, acetaminophen, and an antiemetic prior to therapy to mitigate the risk and severity of infusion-related reactions. Naxitamab may also cause severe neurotoxicity, including significant neuropathic pain, transverse myelitis, reversible posterior leukoencephalopathy syndrome (RPLS), and ocular toxicities. Pain management should be implemented prior to and during therapy - patients should take a 12-day course of neuropathic pain prophylaxis (e.g. gabapentin) starting 4 days prior to infusion, and should receive oral opioids 45-60 minutes prior to infusion and intravenous opioids and/or ketamine as needed thereafter.6

Mechanism of action

Neuroblastomas are neuroendocrine tumors occurring in immature and developing cells of the nervous system and are the most common malignancy diagnosed in children <1 year of age.4 The GD2 disialoganglioside is a glycolipid found highly expressed on the surface of neuroectodermal tumors,5 including neuroblastomas. GD2 exhibits high density and homogeneity across neuroblastomas and a rare occurrence of antigen loss,4 making it a desirable target in the treatment of these cancers.

Naxitamab is an IgG1 monoclonal antibody directed against GD2 disialogangliosides - it binds to GD2 on the surface of neuroblastoma cells and induces both complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC),6 the latter of which is enhanced by co-administration with GM-CSF.4

TargetActionsOrganism
AGD2 disialoganglioside
binder
antibody
Humans
Absorption

The mean plasma concentration of naxitamab following an intravenous infusion of 3 mg/kg over 30 minutes was 57.4 μg/mL.6 The AUC of naxitamab appears to correlate with body size.2

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

While the metabolism of naxitamab has not been studied directly,6 monoclonal antibodies as a class are principally metabolized to smaller peptides via catabolic processes.6,3

Route of elimination

Monoclonal antibodies are typically eliminated via uptake into cells and subsequent catabolism via lysosomal degradation. Due to their large size, they are only eliminated renally under pathologic conditions.3

Half-life

The mean terminal half-life of naxitamab is 8.2 days.6

Clearance

The clearance of naxitamab appears to be correlated inversely with body weight.6

Adverse Effects
Adverseeffects
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Toxicity

Data regarding overdose of naxitamab are unavailable. In the event of an overdose, patients should be treated with symptomatic and supportive measures.

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
AcebutololNaxitamab may decrease the antihypertensive activities of Acebutolol.
AceclofenacThe risk or severity of hypertension can be increased when Aceclofenac is combined with Naxitamab.
AcemetacinThe risk or severity of hypertension can be increased when Acemetacin is combined with Naxitamab.
AcetophenazineAcetophenazine may increase the neurotoxic activities of Naxitamab.
Acetylsalicylic acidThe risk or severity of hypertension can be increased when Acetylsalicylic acid is combined with Naxitamab.
AlclofenacThe risk or severity of hypertension can be increased when Alclofenac is combined with Naxitamab.
AlfentanilThe risk or severity of hypertension can be increased when Alfentanil is combined with Naxitamab.
AlimemazineAlimemazine may increase the neurotoxic activities of Naxitamab.
AliskirenNaxitamab may decrease the antihypertensive activities of Aliskiren.
AlmotriptanThe risk or severity of hypertension can be increased when Almotriptan is combined with Naxitamab.
Interactions
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Food Interactions
No interactions found.

Products

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International/Other Brands
Danyelza
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DanyelzaInjection40 mg/10mLIntravenousY-mAbs Therapeutics, Inc.2020-11-25Not applicableUS flag

Categories

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

Chemical Identifiers

UNII
9K8GNJ2874
CAS number
1879925-92-4

References

General References
  1. Kushner BH, Cheung IY, Modak S, Basu EM, Roberts SS, Cheung NK: Humanized 3F8 Anti-GD2 Monoclonal Antibody Dosing With Granulocyte-Macrophage Colony-Stimulating Factor in Patients With Resistant Neuroblastoma: A Phase 1 Clinical Trial. JAMA Oncol. 2018 Dec 1;4(12):1729-1735. doi: 10.1001/jamaoncol.2018.4005. [Article]
  2. Cheung IY, Kushner BH, Modak S, Basu EM, Roberts SS, Cheung NV: Phase I trial of anti-GD2 monoclonal antibody hu3F8 plus GM-CSF: Impact of body weight, immunogenicity and anti-GD2 response on pharmacokinetics and survival. Oncoimmunology. 2017 Jul 31;6(11):e1358331. doi: 10.1080/2162402X.2017.1358331. eCollection 2017. [Article]
  3. Temrikar ZH, Suryawanshi S, Meibohm B: Pharmacokinetics and Clinical Pharmacology of Monoclonal Antibodies in Pediatric Patients. Paediatr Drugs. 2020 Apr;22(2):199-216. doi: 10.1007/s40272-020-00382-7. [Article]
  4. Cheung NK, Dyer MA: Neuroblastoma: developmental biology, cancer genomics and immunotherapy. Nat Rev Cancer. 2013 Jun;13(6):397-411. doi: 10.1038/nrc3526. [Article]
  5. Zhao Q, Ahmed M, Guo HF, Cheung IY, Cheung NK: Alteration of Electrostatic Surface Potential Enhances Affinity and Tumor Killing Properties of Anti-ganglioside GD2 Monoclonal Antibody hu3F8. J Biol Chem. 2015 May 22;290(21):13017-27. doi: 10.1074/jbc.M115.650903. Epub 2015 Apr 7. [Article]
  6. FDA Approved Drug Products: Danyelza (naxitamab-gqgk) for intravenous infusion [Link]
  7. FDA Approved Drug Products: Unituxin (dinutuximab) for intravenous injection [Link]
  8. FDA Drug Approvals and Databases: FDA grants accelerated approval to naxitamab for high-risk neuroblastoma in bone or bone marrow [Link]
RxNav
2474039
Wikipedia
Naxitamab

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2Active Not RecruitingTreatmentNeuroblastoma (NB)1
2Not Yet RecruitingTreatmentNeuroblastoma (NB)1
2RecruitingTreatmentNeuroblastoma (NB)1
2RecruitingTreatmentRecurrent Neuroblastoma1
2RecruitingTreatmentRecurrent Osteosarcoma1
1Active Not RecruitingTreatmentHigh Risk / Neuroblastoma (NB)1
1Active Not RecruitingTreatmentNeuroblastoma (NB)1
1CompletedTreatmentNeuroblastoma (NB)1
1, 2Active Not RecruitingTreatmentNeuroblastoma (NB)1
1, 2RecruitingTreatmentNeuroblastoma (NB) / Other Solid Tumor Cancers / Sarcoma, Osteogenic1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionIntravenous40 mg/10mL
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

Drugtargets2
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Kind
Small molecule
Organism
Humans
Pharmacological action
Yes
Actions
Binder
Antibody
GD2 is a disialoganglioside that is overexpressed on neuroblastoma cells and other cells of neuroectodermal origin, including the central nervous system and peripheral nerves.
References
  1. FDA Approved Drug Products: Danyelza (naxitamab-gqgk) for intravenous infusion [Link]

Drug created at November 28, 2020 01:24 / Updated at July 02, 2021 03:58