Blinatumomab

Identification

Summary

Blinatumomab is an antineoplastic antibody used to treat CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in relapsed and refractory patients, as well as those in first or second complete remission with minimal residual disease (MRD).

Brand Names
Blincyto
Generic Name
Blinatumomab
DrugBank Accession Number
DB09052
Background

Blinatumomab is a BiTE-class (bi-specific T-cell engager) constructed monoclonal antibody formed by the recombinant fusion of an anti-CD3 single-chain variable fragment (scFV) and an anti-CD19 scFV through a short peptide linker.5,6 CD3 is an antigen expressed on the surface of T-cells, while CD19 is mostly expressed on the surface of malignant B-cells. Since blinatumomab has an affinity to both antigens, it redirects T-cells to tumor cells expressing CD19 and promotes tumor cell lysis and apoptosis.1,2,4

Blinatumomab is manufactured by Amgen Inc. and marketed under the brand Blincyto. It was first approved by the FDA in December 2014 for the treatment of CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in relapsed and refractory patients. In March 2018, it was approved under the FDA’s accelerated approval program for the treatment of CD19-positive B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% in adults and children.6 Full approval for this indication was granted in June 2023.7,8

Blinatumomab has a short half-life, requiring patients to receive a continuous infusion over 4-week cycles using a portable mini-pump for optimum delivery.3

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Structure
Protein Chemical Formula
C2367H3577N649O772S19
Protein Average Weight
54100.0 Da
Sequences
>single chain variable fragment fusion protein 
DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDASNLVS
GIPPRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGGTKLEIKGGGGSGGGG
SGGGGSQVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPG
DGDTNYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYW
GQGTTVTVSSGGGGSDIKLQQSGAELARPGASVKMSCKTSGYTFTRYTMHWVKQRPGQGL
EWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYC
LDYWGQGTTLTVSSVEGGSGGSGGSGGSGGVDDIQLTQSPAIMSASPGEKVTMTCRASSS
VSYMNWYQQKSGTSPKRWIYDTSKVASGVPYRFSGSGSGTSYSLTISSMEAEDAATYYCQ
QWSSNPLTFGAGTKLELKHHHHHH
References:
  1. WHO: International Nonproprietary Names for Pharmaceutical Substances (INN) -List 62 [Link]
Download FASTA Format
Synonyms
  • Blinatumomab
External IDs
  • AMG103
  • MEDI 538
  • MEDI-538
  • MEDI538
  • MT 103
  • MT-103
  • MT103

Pharmacology

Indication

Blinatumomab is indicated for the treatment of adults and children with relapsed or refractory CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL). It is also indicated in adults and children for the treatment of CD19-positive B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%.7

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofB-cell precursor acute lymphoblastic leukemia (all)•••••••••••••••••• •••••••••••••• •• •••••• •••••••• •••••••••• ••••••• •••••••• ••••••• • •••••••••••••
Treatment ofRefractory b-cell precursor acute lymphoblastic leukemia•••••••••••••••••• ••••••••••••••••••
Treatment ofRelapsed b cell precursor acute lymphoblastic leukemia•••••••••••••••••• ••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Blinatumomab promoted peripheral T-cell redistribution at the start of infusion or dose escalation. In most patients, T-cell counts were lower in the first 1-2 days of treatment and returned to baseline levels within 7-14 days. An increase in T-cell levels, also known as T-cell expansion, was observed in a few patients. In the first treatment cycle, blinatumomab doses higher than ≥ 5 mcg/m2/day or ≥ 9 mcg/day decreased peripheral B-cell counts to 10 cells/microliter or less. During the blinatumomab-free period between treatment cycles (2 weeks), peripheral B-cell counts did not recover. The use of blinatumomab may lead to an elevation of IL-6, IL-10, and IFN-γ; however, cytokine levels return to baseline within 24 to 48 hours.6 Blinatumomab may lead to the development of cytokine release syndrome, neurological toxicities, infections, tumor lysis syndrome, neutropenia and febrile neutropenia, pancreatitis, leukoencephalopathy and transient elevations in liver enzymes. The use of blinatumomab can also affect a patient’s ability to drive and use machines.6

Mechanism of action

Blinatumomab is a bispecific T-cell engager (BiTE) that targets CD19, an antigen expressed on the surface of B-cells, and CD3, an antigen expressed on the surface of T-cells.1 B-cell malignancies, such as acute lymphoblastic leukemia (ALL), express high levels of CD19, making it a therapeutic target for the treatment of these conditions. Blinatumomab recruits and activates endogenous T-cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on both benign and malignant B cells.6 By bringing T-cells and tumor cells together, blinatumomab induces an immune response that leads to T-cell activation and proliferation. It promotes the release of cytokines such as TNF-α, IFN-γ, IL-6, and IL-10 by T-cells, the induction of activation markers, such as CD69 and CD25, and the expression of adhesion molecules on the T-cell surface. Altogether, blinatumomab promotes the lysis of CD19+ tumor cells.1,6

TargetActionsOrganism
AB-lymphocyte antigen CD19
antibody
activator
regulator
Humans
AT-cell surface glycoprotein CD3 delta chain
antibody
activator
Humans
Absorption

In adult patients, the pharmacokinetic profile of blinatumomab appears to be linear between 5 to 90 mcg/m2/day (equivalent to 9 to 162 mcg/day). The steady-state serum concentration (Css) of blinatumomab was achieved within a day of continuous intravenous infusion, and in the range tested, the mean Css was approximately dose-proportional. At the clinical doses for the treatment of relapsed or refractory acute lymphoblastic leukemia (9 mcg/day and 28 mcg/day), the Css was 228 (356) pg/mL and 616 (537) pg/mL, respectively.6

Volume of distribution

Blinatumomab has a volume of distribution based on terminal phase of 4.35 L.6

Protein binding

Not Available

Metabolism

The metabolic pathway of blinatumomab has not been characterized. As a monoclonal antibody, blinatumomab is expected to be metabolized into small peptides and amino acids via catabolic pathways.6

Route of elimination

At clinical doses, negligible amounts of blinatumomab were excreted in the urine.6

Half-life

Blinatumomab has a half-life of 2.10 hours. In pediatric patients, the half-life was 2.19 hours in the first cycle of blinatumomab at the recommended dose.6

Clearance

Blinatumomab has an estimated systemic clearance of 3.11 L/hour in patients receiving blinatumomab with continuous intravenous infusion. There is a 2-fold difference in clearance values between patients with normal renal function and those with moderate renal impairment. Pediatric patients had an estimated clearance of 1.88 L/hour/m2 in the first cycle of blinatumomab at the recommended dose.6

Adverse Effects
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Toxicity

Blinatumomab overdose cases have been reported, including a patient that received 133-fold the recommended therapeutic dose over a short period of time. In a study that included pediatric and adolescent patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), a patient receiving 30 mcg/m2/day of blinatumomab (higher than the maximum tolerated dose) experienced a fatal cardiac failure event in the setting of life-threatening cytokine release syndrome (CRS).6 The adverse reactions observed during blinatumomab overdoses included fever, tremors, and headache, consistent with those observed at the recommended dose. If a patient is experiencing an overdose, the blinatumomab product label recommends to interrupt the infusion, monitor the patient for signs of adverse reactions, and provide supportive care. Re-initiating blinatumomab at the recommended dose should be considered after all adverse reactions have been resolved and no earlier than 12 hours after the infusion is interrupted.6 The carcinogenic, genotoxic, and fertility effects of blinatumomab have not been evaluated.6

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
AbataceptThe risk or severity of adverse effects can be increased when Abatacept is combined with Blinatumomab.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Blinatumomab.
AcenocoumarolThe risk or severity of bleeding can be increased when Acenocoumarol is combined with Blinatumomab.
Acetylsalicylic acidThe risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Blinatumomab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Blinatumomab.
Food Interactions
No interactions found.

Products

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International/Other Brands
Blincyto (Amgen Inc.)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
BlincytoPowder, for solution38.5 mcg / vialIntravenousAmgen2016-03-17Not applicableCanada flag
BlincytoInjection, powder, lyophilized, for solution; Kit12.5 ug/1mLIntravenousAMGEN INC2014-12-18Not applicableUS flag
BlincytoSolution38.5 mcgIntravenousAmgen Europe B.V.2020-12-22Not applicableEU flag

Categories

ATC Codes
L01FX07 — Blinatumomab
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
4FR53SIF3A
CAS number
853426-35-4

References

Synthesis Reference

Kufer, P et al. (2017). Anti-leukocyte adhesion for the mitigation of potential adverse events caused by CD3-specific binding domains. (U.S. Patent No. 9,688,760 B2). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/a1/59/c9/e0a1c48f125447/US9688760.pdf

General References
  1. Zugmaier G, Klinger M, Schmidt M, Subklewe M: Clinical overview of anti-CD19 BiTE((R)) and ex vivo data from anti-CD33 BiTE((R)) as examples for retargeting T cells in hematologic malignancies. Mol Immunol. 2015 Oct;67(2 Pt A):58-66. doi: 10.1016/j.molimm.2015.02.033. Epub 2015 Apr 13. [Article]
  2. Garber K: Bispecific antibodies rise again. Nat Rev Drug Discov. 2014 Nov;13(11):799-801. doi: 10.1038/nrd4478. [Article]
  3. Thomas X: Blinatumomab: a new era of treatment for adult ALL? Lancet Oncol. 2015 Jan;16(1):6-7. doi: 10.1016/S1470-2045(14)71183-0. Epub 2014 Dec 16. [Article]
  4. Topp MS, Gokbuget N, Stein AS, Zugmaier G, O'Brien S, Bargou RC, Dombret H, Fielding AK, Heffner L, Larson RA, Neumann S, Foa R, Litzow M, Ribera JM, Rambaldi A, Schiller G, Bruggemann M, Horst HA, Holland C, Jia C, Maniar T, Huber B, Nagorsen D, Forman SJ, Kantarjian HM: Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015 Jan;16(1):57-66. doi: 10.1016/S1470-2045(14)71170-2. Epub 2014 Dec 16. [Article]
  5. Wong R, Pepper C, Brennan P, Nagorsen D, Man S, Fegan C: Blinatumomab induces autologous T-cell killing of chronic lymphocytic leukemia cells. Haematologica. 2013 Dec;98(12):1930-8. doi: 10.3324/haematol.2012.082248. Epub 2013 Jun 28. [Article]
  6. FDA Approved Drug Products: BLINCYTO (blinatumomab) for injection, for intravenous use [Link]
  7. FDA Approved Drug Products: BLINCYTO (blinatumomab) for injection, for intravenous use (June 2023) [Link]
  8. BioSpace: FDA grants full approval for BLINCYTO (blinatumomab) to treat minimal residual disease-positive B-cell precursor acute lymphoblastic leukemia [Link]
  9. FDA Approved Drug Products: BLINCYTO® (blinatumomab) for injection, for intravenous use (Feb 2024) [Link]
KEGG Drug
D09325
PubChem Substance
347910400
RxNav
1597258
ChEMBL
CHEMBL1742992
Drugs.com
Drugs.com Drug Page
Wikipedia
Blinatumomab

Clinical Trials

Clinical Trials

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous38.5 mcg/1vial
Injection, powder, lyophilized, for solution; kitIntravenous12.5 ug/1mL
PowderIntravenous; Parenteral38.5 MICROGRAMMI
Powder, for solutionIntravenous38.5 mcg / vial
SolutionIntravenous38.5 mcg
InjectionIntravenous
InjectionParenteral38.5 mcg
Injection, powder, lyophilized, for solutionIntravenous55 mcg/ml
Injection, powder, lyophilized, for solutionIntravenous38.5 mcg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7235641No2007-06-262023-12-22US flag
US7575923No2009-08-182018-04-21US flag
US7635472No2009-12-222023-05-31US flag
US8247194No2012-08-212024-05-05US flag
US20120328618No2009-10-272029-10-27US flag
US20130323247No2008-11-072028-11-07US flag

Properties

State
Solid
Experimental Properties
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antibody
Activator
Regulator
General Function
Receptor signaling protein activity
Specific Function
Assembles with the antigen receptor of B-lymphocytes in order to decrease the threshold for antigen receptor-dependent stimulation.
Gene Name
CD19
Uniprot ID
P15391
Uniprot Name
B-lymphocyte antigen CD19
Molecular Weight
61127.985 Da
References
  1. Zugmaier G, Klinger M, Schmidt M, Subklewe M: Clinical overview of anti-CD19 BiTE((R)) and ex vivo data from anti-CD33 BiTE((R)) as examples for retargeting T cells in hematologic malignancies. Mol Immunol. 2015 Oct;67(2 Pt A):58-66. doi: 10.1016/j.molimm.2015.02.033. Epub 2015 Apr 13. [Article]
  2. Schnaiter A, Stilgenbauer S: Refractory chronic lymphocytic leukemia--new therapeutic strategies. Oncotarget. 2010 Nov;1(7):472-82. doi: 10.18632/oncotarget.101103. [Article]
  3. FDA Approved Drug Products: BLINCYTO (blinatumomab) for injection, for intravenous use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antibody
Activator
General Function
Transmembrane signaling receptor activity
Specific Function
The CD3 complex mediates signal transduction.
Gene Name
CD3D
Uniprot ID
P04234
Uniprot Name
T-cell surface glycoprotein CD3 delta chain
Molecular Weight
18929.38 Da
References
  1. Zugmaier G, Klinger M, Schmidt M, Subklewe M: Clinical overview of anti-CD19 BiTE((R)) and ex vivo data from anti-CD33 BiTE((R)) as examples for retargeting T cells in hematologic malignancies. Mol Immunol. 2015 Oct;67(2 Pt A):58-66. doi: 10.1016/j.molimm.2015.02.033. Epub 2015 Apr 13. [Article]
  2. FDA Approved Drug Products: BLINCYTO (blinatumomab) for injection, for intravenous use [Link]

Drug created at May 06, 2015 22:29 / Updated at February 14, 2024 00:55