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:

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

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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 Type	Indication	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	B-cell precursor acute lymphoblastic leukemia (all)	••••••••••••	•••••• •••••••••	••••• •• •••••• •••••••• •••••••••• ••••••• •••••••• ••••••• • ••••	•••••••••
Treatment of	Refractory b-cell precursor acute lymphoblastic leukemia	••••••••••••	•••••• •••••••••		•••••••••
Treatment of	Relapsed 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

Target	Actions	Organism
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 (C_ss) of blinatumomab was achieved within a day of continuous intravenous infusion, and in the range tested, the mean C_ss 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 C_ss 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 Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">

Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">

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.

Drug	Interaction
Integrate drug-drug interactions in your software
Abatacept	The risk or severity of adverse effects can be increased when Abatacept is combined with Blinatumomab.
Abciximab	The risk or severity of bleeding can be increased when Abciximab is combined with Blinatumomab.
Acenocoumarol	The risk or severity of bleeding can be increased when Acenocoumarol is combined with Blinatumomab.
Acetylsalicylic acid	The risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Blinatumomab.
Adalimumab	The 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

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Blincyto	Powder, for solution	38.5 mcg / vial	Intravenous	Amgen	2016-03-17	Not applicable
Blincyto	Injection, powder, lyophilized, for solution; Kit	12.5 ug/1mL	Intravenous	AMGEN INC	2014-12-18	Not applicable
Blincyto	Solution	38.5 mcg	Intravenous	Amgen Europe B.V.	2020-12-22	Not applicable

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

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]
Garber K: Bispecific antibodies rise again. Nat Rev Drug Discov. 2014 Nov;13(11):799-801. doi: 10.1038/nrd4478. [Article]
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]
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]
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]
FDA Approved Drug Products: BLINCYTO (blinatumomab) for injection, for intravenous use [Link]
FDA Approved Drug Products: BLINCYTO (blinatumomab) for injection, for intravenous use (June 2023) [Link]
BioSpace: FDA grants full approval for BLINCYTO (blinatumomab) to treat minimal residual disease-positive B-cell precursor acute lymphoblastic leukemia [Link]
FDA Approved Drug Products: BLINCYTO® (blinatumomab) for injection, for intravenous use (Feb 2024) [Link]

External Links

KEGG Drug: D09325
PubChem Substance: 347910400
RxNav: 1597258
ChEMBL: CHEMBL1742992
Drugs.com: Drugs.com Drug Page
Wikipedia: Blinatumomab

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Recruiting	Treatment	Precursor B-lymphoblastic leukaemia acute	1
3	Active Not Recruiting	Treatment	Acute Lymphoblastic Leukaemias (ALL) / B Acute Lymphoblastic Leukemia, Philadelphia Chromosome Negative	1
3	Active Not Recruiting	Treatment	Recurrent B Acute Lymphoblastic Leukemia	1
3	Completed	Treatment	Acute Lymphoblastic Leukaemias (ALL)	2
3	Not Yet Recruiting	Treatment	Acute Lymphoblastic Leukaemias (ALL) / Mixed Phenotype Acute Leukemia (MPAL)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, powder, lyophilized, for solution	Intravenous	38.5 mcg/1vial
Injection, powder, lyophilized, for solution; kit	Intravenous	12.5 ug/1mL
Powder	Intravenous; Parenteral	38.5 MICROGRAMMI
Powder, for solution	Intravenous	38.5 mcg / vial
Solution	Intravenous	38.5 mcg
Injection	Intravenous
Injection	Parenteral	38.5 mcg
Injection, powder, lyophilized, for solution	Intravenous	55 mcg/ml
Injection, powder, lyophilized, for solution	Intravenous	38.5 mcg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US7235641	No	2007-06-26	2023-12-22
US7575923	No	2009-08-18	2018-04-21
US7635472	No	2009-12-22	2023-05-31
US8247194	No	2012-08-21	2024-05-05
US20120328618	No	2009-10-27	2029-10-27
US20130323247	No	2008-11-07	2028-11-07

Properties

State: Solid
Experimental Properties: Not Available

Targets

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Details1. B-lymphocyte antigen CD19

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

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]
Schnaiter A, Stilgenbauer S: Refractory chronic lymphocytic leukemia--new therapeutic strategies. Oncotarget. 2010 Nov;1(7):472-82. doi: 10.18632/oncotarget.101103. [Article]
FDA Approved Drug Products: BLINCYTO (blinatumomab) for injection, for intravenous use [Link]

Details2. T-cell surface glycoprotein CD3 delta chain

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

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]
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

Blinatumomab

Identification

References:

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Targets

References

References