Benralizumab

Identification

Summary

Benralizumab is a monoclonal antibody used to treat eosinophilic asthma.

Brand Names
Fasenra
Generic Name
Benralizumab
DrugBank Accession Number
DB12023
Background

Benralizumab is a humanized recombinant monoclonal antibody of the isotype IgG1k immunoglobulin that specifically binds to the alpha chain of the interleukin 5 receptor (IL-5R) expressed on eosinophils and basophils.2 It inhibits the binding of IL-5 as well as the hetero-oligomerization of the alpha and beta subunits of the IL-5R, thus blocking, signal transduction. Besides, it is an afucosylated IgG which gives it high affinity for the FcγRIIIα receptor in natural killer cells, macrophages and neutrophils.1 Benralizumab, FDA approved on November 14, 2017, was developed by MedImmune, the AstraZeneca's global biologic research and development arm.6

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Structure
Protein Chemical Formula
C6492H10060N1724O2028S42
Protein Average Weight
146054.0 Da
Sequences
>Heavy chain 
EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYVIHWVRQRPGQGLAWMGYINPYNDGTKY
NERFKGKVTITSDRSTSTVYMELSSLRSEDTAVYLCGREGIRYYGLLGDYWGQGTLVTVS
SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS
SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG
GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY
NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR
WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>Light chain
DIQMTQSPSSLSASVGDRVTITCGTSEDIINYLNWYQQKPGKAPKLLIYHTSRLQSGVPS
RFSGSGSGTDFTLTISSLQPEDFATYYCQQGYTLPYTFGQGTKVEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
Download FASTA Format
Synonyms
  • Benralizumab
External IDs
  • BIW-8405
  • MEDI-563

Pharmacology

Indication

Benralizumab is indicated as a maintenance treatment of patients 12 years or older with severe asthma and an eosinophilic phenotype.7 The pathology of severe asthma with eosinophilic phenotype is also denotated as TH2-high phenotype. The patients with this phenotype are characterized by the expression of IL-5 and IL-13, airway hyperresponsiveness, responsiveness to inhaled corticosteroids, high serum IgE and eosinophilia in blood and airway. In the TH2-high phenotype, IL-5 presents a central role as it is responsible for eosinophil differentiation, survival, activation and migration to the lungs.3

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Adjunct therapy in treatment ofSevere eosinophilic asthma••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Eosinophils are the key target of inflammatory respiratory diseases and they undergo apoptosis in absence of IL-5. Therefore, benralizumab action on the IL-5 receptor in basophils and eosinophils produces the apoptosis and its significant reduction in the blood.2 On the other hand, Benralizumab binding to natural killer cells FcγRIIIα receptor produces a direct antibody-dependent cell-mediated cytotoxicity. All these effects produce a reduction in eosinophil count in airway mucosa, submucosa, sputum, blood and bone marrow.4

Mechanism of action

Interleukin-5 (IL-5) induces an eosinophil-mediated inflammatory response by binding to the IL-5 receptor (IL-5R) expressed in eosinophils, basophils and some mast cells. Benralizumab, unlike IL-5 low-affinity binding, binds with high affinity to the domain I of the α-chain of IL-5R and blocks its signaling and the proliferation of IL-5-dependent cell lines. On the other hand, Benralizumab is an afucosylated antibody in the CH2 region which gives it a high affinity for the FcγRIIIa on natural killer cells, macrophages and neutrophils. This binding triggers a magnified apoptosis response in eosinophils via antibody-dependent cell-mediated cytotoxicity.1,3

TargetActionsOrganism
AInterleukin-5 receptor subunit alpha
antibody
Humans
ALow affinity immunoglobulin gamma Fc region receptor III-A
binding
Humans
Absorption

Subcutaneous administration of Benralizumab presented a dose-proportional pharmacokinetic profile. The administration of 20-200 mg presented an absorption half-life of 3.6 days with a bioavailability of 58%.Label It is also reported for Benralizumab a Cmax of 82 mcg/ml and AUC of 775 mcg day/ml.1

Volume of distribution

Pharmacokinetic reports of Benralizumab showed a volume of distribution in a range of 52-93ml/kg. For a 70kg individual, the central volume of distribution of Benralizumab is 3.2 L while the peripheral volume of distribution is reported to be 2.5 L.5

Protein binding

There is no reports indicating that Benralizumab binds to plasma proteins.

Metabolism

As any monoclonal IgG antibody, Beralizumab is degraded by proteases widely spread in the body. Label

Route of elimination

Benraluzimab presents a linear pharmacokinetic without target-receptor mediated clearance.Label The presence of a dose-proportional pharmacokinetics suggests a rapid depletion of the target and an elimination mainly mediated through the reticuloendothelial system.5

Half-life

The half-life of Benralizumab is estimated to be 15-18 days.1

Clearance

For a subject weighting 70kg, the typical systemic clearance is 0.29L/day.Label

Adverse Effects
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Toxicity

There are not reports of long-term studies regarding tumorgenesis or carcinogenesis. Fertility studies performed in aminal trials showed no adverse histopathological findings.Label

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
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Benralizumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Benralizumab.
AducanumabThe risk or severity of adverse effects can be increased when Benralizumab is combined with Aducanumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Benralizumab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Benralizumab.
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
FasenraInjection, solution30 mg/1mLSubcutaneousAstraZeneca Pharmaceuticals LP2019-10-04Not applicableUS flag
FasenraInjection, solution30 mg/1mLSubcutaneousAstraZeneca Pharmaceuticals LP2017-11-14Not applicableUS flag
FasenraInjection, solution30 mgSubcutaneousAstra Zeneca Ab2020-12-16Not applicableEU flag
FasenraSolution30 mg / mLSubcutaneousAstra Zeneca2018-03-28Not applicableCanada flag
FasenraInjection, solution30 mgSubcutaneousAstra Zeneca Ab2020-12-16Not applicableEU flag

Categories

ATC Codes
R03DX10 — Benralizumab
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
71492GE1FX
CAS number
1044511-01-4

References

General References
  1. Ghazi A, Trikha A, Calhoun WJ: Benralizumab--a humanized mAb to IL-5Ralpha with enhanced antibody-dependent cell-mediated cytotoxicity--a novel approach for the treatment of asthma. Expert Opin Biol Ther. 2012 Jan;12(1):113-8. doi: 10.1517/14712598.2012.642359. Epub 2011 Dec 5. [Article]
  2. Laviolette M, Gossage DL, Gauvreau G, Leigh R, Olivenstein R, Katial R, Busse WW, Wenzel S, Wu Y, Datta V, Kolbeck R, Molfino NA: Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J Allergy Clin Immunol. 2013 Nov;132(5):1086-1096.e5. doi: 10.1016/j.jaci.2013.05.020. Epub 2013 Jul 16. [Article]
  3. Bagnasco D, Ferrando M, Varricchi G, Puggioni F, Passalacqua G, Canonica GW: Anti-Interleukin 5 (IL-5) and IL-5Ra Biological Drugs: Efficacy, Safety, and Future Perspectives in Severe Eosinophilic Asthma. Front Med (Lausanne). 2017 Aug 31;4:135. doi: 10.3389/fmed.2017.00135. eCollection 2017. [Article]
  4. Tan LD, Bratt JM, Godor D, Louie S, Kenyon NJ: Benralizumab: a unique IL-5 inhibitor for severe asthma. J Asthma Allergy. 2016 Apr 4;9:71-81. doi: 10.2147/JAA.S78049. eCollection 2016. [Article]
  5. Wang B, Yan L, Yao Z, Roskos LK: Population Pharmacokinetics and Pharmacodynamics of Benralizumab in Healthy Volunteers and Patients With Asthma. CPT Pharmacometrics Syst Pharmacol. 2017 Apr;6(4):249-257. doi: 10.1002/psp4.12160. Epub 2017 Jan 21. [Article]
  6. Newswire [Link]
  7. Astra Zeneca news [Link]
PubChem Substance
347911271
Wikipedia
Benralizumab
FDA label
Download (858 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentAsthma1
4CompletedTreatmentAsthma / Severe Eosinophilic Asthma1
4CompletedTreatmentChronic Idiopathic Urticaria1
4CompletedTreatmentIn Adult Patients of Severe Asthma With Eosinophilic Phenotype in India1
4RecruitingOtherEosinophilic Asthma / Severe Asthma1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionParenteral; Subcutaneous30 MG
Injection, solutionSubcutaneous30 mg/1mL
Injection, solutionSubcutaneous30 mg
SolutionSubcutaneous30 mg / mL
Injection, solutionSubcutaneous
Injection, solution30 mg/ml
SolutionSubcutaneous30 mg
Injection, solutionSubcutaneous30 mg/ml
Injection, solution30 mg/1ml
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)69 °C (midpoint transition), 80 °C (whole IgG1)Dashivets, et al. PLOS ONE. 10. e0143520. 10.1371/journal.pone.0143520. (2015).
isoelectric point6.6 - 7.2Jin, et al. Electrophoresis. Sep;23(19):3385-91. (2002).

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antibody
General Function
Interleukin-5 receptor activity
Specific Function
This is the receptor for interleukin-5. The alpha chain binds to IL5.
Gene Name
IL5RA
Uniprot ID
Q01344
Uniprot Name
Interleukin-5 receptor subunit alpha
Molecular Weight
47684.225 Da
References
  1. Ghazi A, Trikha A, Calhoun WJ: Benralizumab--a humanized mAb to IL-5Ralpha with enhanced antibody-dependent cell-mediated cytotoxicity--a novel approach for the treatment of asthma. Expert Opin Biol Ther. 2012 Jan;12(1):113-8. doi: 10.1517/14712598.2012.642359. Epub 2011 Dec 5. [Article]
  2. Laviolette M, Gossage DL, Gauvreau G, Leigh R, Olivenstein R, Katial R, Busse WW, Wenzel S, Wu Y, Datta V, Kolbeck R, Molfino NA: Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J Allergy Clin Immunol. 2013 Nov;132(5):1086-1096.e5. doi: 10.1016/j.jaci.2013.05.020. Epub 2013 Jul 16. [Article]
  3. Bagnasco D, Ferrando M, Varricchi G, Puggioni F, Passalacqua G, Canonica GW: Anti-Interleukin 5 (IL-5) and IL-5Ra Biological Drugs: Efficacy, Safety, and Future Perspectives in Severe Eosinophilic Asthma. Front Med (Lausanne). 2017 Aug 31;4:135. doi: 10.3389/fmed.2017.00135. eCollection 2017. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binding
General Function
Not Available
Specific Function
Receptor for the Fc region of IgG. Binds complexed or aggregated IgG and also monomeric IgG. Mediates antibody-dependent cellular cytotoxicity (ADCC) and other antibody-dependent responses, such as...
Gene Name
FCGR3A
Uniprot ID
P08637
Uniprot Name
Low affinity immunoglobulin gamma Fc region receptor III-A
Molecular Weight
29088.895 Da
References
  1. Ghazi A, Trikha A, Calhoun WJ: Benralizumab--a humanized mAb to IL-5Ralpha with enhanced antibody-dependent cell-mediated cytotoxicity--a novel approach for the treatment of asthma. Expert Opin Biol Ther. 2012 Jan;12(1):113-8. doi: 10.1517/14712598.2012.642359. Epub 2011 Dec 5. [Article]
  2. Laviolette M, Gossage DL, Gauvreau G, Leigh R, Olivenstein R, Katial R, Busse WW, Wenzel S, Wu Y, Datta V, Kolbeck R, Molfino NA: Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J Allergy Clin Immunol. 2013 Nov;132(5):1086-1096.e5. doi: 10.1016/j.jaci.2013.05.020. Epub 2013 Jul 16. [Article]
  3. Wang B, Yan L, Yao Z, Roskos LK: Population Pharmacokinetics and Pharmacodynamics of Benralizumab in Healthy Volunteers and Patients With Asthma. CPT Pharmacometrics Syst Pharmacol. 2017 Apr;6(4):249-257. doi: 10.1002/psp4.12160. Epub 2017 Jan 21. [Article]

Drug created at October 20, 2016 21:11 / Updated at June 03, 2022 07:24