Identification

Name
Benralizumab
Accession Number
DB12023  (DB06024)
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

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]

Protein structure
Db12023
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
Not Available
External IDs
BIW-8405 / MEDI-563
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
FasenraSolution30 mgSubcutaneousAstra Zeneca2018-03-28Not applicableCanada
FasenraInjection, solution30 mg/1mLSubcutaneousAstraZeneca Pharmaceuticals LP2017-11-14Not applicableUs
Categories
UNII
71492GE1FX
CAS number
1044511-01-4

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]

Associated Conditions
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
Human
ALow affinity immunoglobulin gamma Fc region receptor III-A
binding
Human
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]

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]

Affected organisms
  • Humans and other mammals
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 Benralizumab.
AbituzumabThe risk or severity of adverse effects can be increased when Benralizumab is combined with Abituzumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Benralizumab.
AdecatumumabThe risk or severity of adverse effects can be increased when Adecatumumab is combined with Benralizumab.
AducanumabThe risk or severity of adverse effects can be increased when Benralizumab is combined with Aducanumab.
AfelimomabThe risk or severity of adverse effects can be increased when Afelimomab is combined with Benralizumab.
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.
AmatuximabThe risk or severity of adverse effects can be increased when Benralizumab is combined with Amatuximab.
AMG 108The risk or severity of adverse effects can be increased when AMG 108 is combined with Benralizumab.
Food Interactions
Not Available

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. [PubMed:22136436]
  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. [PubMed:23866823]
  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. [PubMed:28913336]
  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. [PubMed:27110133]
  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. [PubMed:28109128]
  6. Newswire [Link]
  7. Astra Zeneca news [Link]
External Links
PubChem Substance
347911271
Wikipedia
Benralizumab
AHFS Codes
  • 48:92.00 — Respiratory Agents, Miscellaneous
FDA label
Download (858 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableAsthma Bronchial1
1CompletedTreatmentAsthma Bronchial1
1CompletedTreatmentAsthma Bronchial / Chronic Obstructive Pulmonary Disease (COPD)1
1, 2RecruitingTreatmentEosinophilic Gastritis or Gastroenteritis1
2Active Not RecruitingTreatmentHypereosinophilic Syndromes1
2CompletedTreatmentAsthma Bronchial3
2CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD) / Pulmonary Disease, Chronic Obstructive1
2CompletedTreatmentEosinophilic Chronic Rhinosinusitis1
2Not Yet RecruitingTreatmentAtopic Dermatitis (AD) / Dermatitis, Eczematous / Genetic Diseases, Inborn / Hypersensitivity / Hypersensitivity, Immediate / Immune System Diseases / Skin Diseases / Skin Diseases, Eczematous / Skin Diseases, Genetic / Skin Inflammation1
2RecruitingTreatmentAsthma Bronchial1
2RecruitingTreatmentChronic Rhinosinusitis (Diagnosis) / Eosinophilia / Polyps, Nasal1
3Active Not RecruitingOtherAsthma Bronchial1
3CompletedOtherAsthma Bronchial2
3CompletedSupportive CareAsthma Bronchial1
3CompletedTreatmentAsthma Bronchial6
3Not Yet RecruitingTreatmentAsthma, Exercise-Induced1
3RecruitingTreatmentAsthma Bronchial4
3RecruitingTreatmentPolyps, Nasal1
3RecruitingTreatmentSevere Prednisone Dependent Eosinophilic Asthma1
3TerminatedTreatmentAsthma Bronchial1
4Not Yet RecruitingBasic ScienceSevere Eosinophilic Asthma1
4RecruitingTreatmentChronic Idiopathic Urticaria1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionSubcutaneous30 mg/1mL
SolutionSubcutaneous30 mg
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).

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
Protein
Organism
Human
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. [PubMed:22136436]
  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. [PubMed:23866823]
  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. [PubMed:28913336]
Kind
Protein
Organism
Human
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. [PubMed:22136436]
  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. [PubMed:23866823]
  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. [PubMed:28109128]

Drug created on October 20, 2016 15:11 / Updated on December 16, 2018 23:30