Inotuzumab ozogamicin
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Identification
- Summary
Inotuzumab ozogamicin is an antibody-drug conjugate used to treat B-cell precursor acute lymphoblastic leukemia (ALL).
- Brand Names
- Besponsa
- Generic Name
- Inotuzumab ozogamicin
- DrugBank Accession Number
- DB05889
- Background
Inotuzumab ozogamicin is an antibody-drug conjugate consisting of a humanized IgG4 kappa CD22-targeting monoclonal antibody covalently attached to calicheamicin derivative, N-acetyl-gamma-calicheamicin dimethylhydrazide.3 The antibody portion of the drug binds to CD22 receptors expressed on leukemic B cells and intracellularly releases N-acetyl-gamma-calicheamicin dimethylhydrazide, which produces cytotoxic effects.3
Inotuzumab ozogamicin was first approved by the European Commission in June 2017 for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).7 A month later, inotuzumab ozogamicin was also approved by the FDA.8
- Type
- Biotech
- Groups
- Approved, Investigational
- Biologic Classification
- Protein Based Therapies
Monoclonal antibody (mAb) - Protein Chemical Formula
- Not Available
- Protein Average Weight
- Not Available
- Sequences
- Not Available
- Synonyms
- Inotuzumab ozogamicin
- External IDs
- CMC 544
- CMC-544
- CMC544
- PF-05208773
- WAY-207294
Pharmacology
- Indication
In the US, inotuzumab ozogamicin is indicated for the treatment of relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL) in adult and pediatric patients one year and older.8
In Europe, it is indicated as monotherapy for the treatment of adults with relapsed or refractory CD22-positive B cell precursor ALL. Patients with Philadelphia chromosome positive (Ph+) relapsed or refractory B cell precursor ALL should have failed treatment with at least 1 tyrosine kinase inhibitor (TKI).7
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Refractory cd22-positive b-cell precursor acute lymphoblastic leukemia (all) •••••••••••• ••••• Treatment of Refractory cd22-positive b-cell precursor acute lymphoblastic leukemia (all) •••••••••••• Treatment of Relapsed cd22-positive b-cell precursor acute lymphoblastic leukemia (all) •••••••••••• ••••• Treatment of Relapsed cd22-positive b-cell precursor acute lymphoblastic leukemia (all) •••••••••••• - Associated Therapies
- Contraindications & Blackbox Warnings
- Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API
- Pharmacodynamics
Inotuzumab ozogamicin is an antineoplastic agent that works to deplete CD22-positive leukemic cells.8 In preclinical models, it arrested tumour growth and reduced the number of ALL cells.1
In clinical trials, inotuzumab ozogamicin was shown to prolong the QT interval.8
- Mechanism of action
Leukemic cells express several lineage-specific antigens, with CD22 being one of the most common antigens identified on the surface of mature and immature B cells.3,4,5
Inotuzumab ozogamicin is a CD22-directed antibody-drug conjugate (ADC) composed of a CD22-directed humanized monoclonal IgG4 antibody linked to a N-acetyl-gamma-calicheamicin, a DNA-binding cytotoxic agent, via a linker.8 The antibody portion of the drug binds to CD22-expressing tumour cells, leading to internalization of the drug-CD22 complex forming an endosome.3,8 The endosome fuses with lysosomes, causing the hydrolytic cleavage of the linker and the intracellular release of N-acetyl-gamma-calicheamicin into the cell.3 N-acetyl-gamma-calicheamicin binds to the minor groove of the DNA in a sequence-specific manner and induces double-strand DNA breaks in tumour cells,3,4 ultimately causing cell cycle arrest and apoptotic cell death.6,8
Target Actions Organism AB-cell receptor CD22 antibodyregulatorHumans - Absorption
Inotuzumab ozogamicin is intended to be administered in cycles that each run for 3 to 4 weeks.7 The mean Cmax of inotuzumab ozogamicin was 308 ng/mL. The mean simulated total AUC per cycle was 100,000 ngxh/mL. In patients with relapsed or refractory ALL, steady-state drug concentration was achieved by Cycle 4. Following administration of multiple doses, a 5.3 times accumulation of inotuzumab ozogamicin was predicted by Cycle 4.8
- Volume of distribution
In humans, the total volume of distribution of inotuzumab ozogamicin was approximately 12 L.7,8
- Protein binding
N-acetyl-gamma-calicheamicin dimethylhydrazide is approximately 97% bound to human plasma proteins in vitro.7,8
- Metabolism
In vitro, N-acetyl-gamma-calicheamicin dimethylhydrazide was primarily metabolized via nonenzymatic reduction.7,8 In humans, N acetyl-gamma-calicheamicin dimethylhydrazide serum levels were typically below the limit of quantitation of 50 pg/mL;7,8 however, sporadic measurable levels of unconjugated calicheamicin up to 276 pg/mL occurred in some patients.7 The antibody portion of the drug is thought to undergo proteolytic degradation into amino acids then recycled into other proteins.2
- Route of elimination
Not Available
- Half-life
In patients with relapsed or refractory ALL, the terminal half-life was 12.3 days.7,8
- Clearance
The pharmacokinetics of inotuzumab ozogamicin were well characterized by a 2-compartment model with linear and time-dependent clearance components. The clearance of inotuzumab ozogamicin at steady state is 0.0333 L/h in patients with relapsed or refractory ALL.7,8
- Adverse Effects
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- Toxicity
There is limited clinical experience regarding the acute toxicity of inotuzumab ozogamicin. Overdoses may result in adverse reactions that are consistent with the reactions observed at the recommended therapeutic dose. In the event of an overdose, drug infusion should be temporarily interrupted, and patients should be monitored for liver and hematological toxicities. Re-initiation of the drug at the correct therapeutic dose should be considered when all toxicities have resolved.7
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbciximab The risk or severity of adverse effects can be increased when Abciximab is combined with Inotuzumab ozogamicin. Acebutolol The risk or severity of QTc prolongation can be increased when Acebutolol is combined with Inotuzumab ozogamicin. Acrivastine The risk or severity of QTc prolongation can be increased when Acrivastine is combined with Inotuzumab ozogamicin. Adagrasib The risk or severity of QTc prolongation can be increased when Adagrasib is combined with Inotuzumab ozogamicin. Adalimumab The risk or severity of adverse effects can be increased when Adalimumab is combined with Inotuzumab ozogamicin. - Food Interactions
- No interactions found.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Besponsa Injection, powder, lyophilized, for solution 0.25 mg/1mL Intravenous Wyeth Pharmaceuticals Llc, a Subsidiary of Pfizer Inc. 2017-08-18 Not applicable US Besponsa Injection, powder, for solution 1 mg Intravenous Pfizer Europe Ma Eeig 2020-12-23 Not applicable EU Besponsa Powder, for solution 0.9 mg / vial Intravenous Pfizer Italia S.R.L. 2018-05-03 Not applicable Canada
Categories
- ATC Codes
- L01FB01 — Inotuzumab ozogamicin
- Drug Categories
- Amino Acids, Peptides, and Proteins
- Antibiotics, Antineoplastic
- Antibodies
- Antibodies, Monoclonal
- Antibodies, Monoclonal, Humanized
- Antibody-drug Conjugates
- Antineoplastic Agents
- Antineoplastic Agents, Immunological
- Antineoplastic and Immunomodulating Agents
- Blood Proteins
- Calicheamicins
- Cancer immunotherapy
- Carbohydrates
- CD22 (Clusters of Differentiation 22) inhibitors
- CD22-directed Antibody Interactions
- CD22-directed Immunoconjugate
- Decreased DNA Integrity
- Globulins
- Glycosides
- Hepatotoxic Agents
- Immunoconjugates
- Immunoglobulins
- Immunologic Factors
- Immunoproteins
- Immunotherapy
- Immunotoxins
- Increased Cellular Death
- Monoclonal antibodies and antibody drug conjugates
- Narrow Therapeutic Index Drugs
- Noxae
- P-glycoprotein substrates
- P-glycoprotein substrates with a Narrow Therapeutic Index
- Proteins
- QTc Prolonging Agents
- Serum Globulins
- Toxic Actions
- 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
- P93RUU11P7
- CAS number
- 635715-01-4
References
- General References
- Dijoseph JF, Dougher MM, Armellino DC, Evans DY, Damle NK: Therapeutic potential of CD22-specific antibody-targeted chemotherapy using inotuzumab ozogamicin (CMC-544) for the treatment of acute lymphoblastic leukemia. Leukemia. 2007 Nov;21(11):2240-5. Epub 2007 Jul 26. [Article]
- Han TH, Zhao B: Absorption, distribution, metabolism, and excretion considerations for the development of antibody-drug conjugates. Drug Metab Dispos. 2014 Nov;42(11):1914-20. doi: 10.1124/dmd.114.058586. Epub 2014 Jul 21. [Article]
- Yilmaz M, Richard S, Jabbour E: The clinical potential of inotuzumab ozogamicin in relapsed and refractory acute lymphocytic leukemia. Ther Adv Hematol. 2015 Oct;6(5):253-61. doi: 10.1177/2040620715596715. [Article]
- Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gokbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS: Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. doi: 10.1056/NEJMoa1509277. Epub 2016 Jun 12. [Article]
- Thota S, Advani A: Inotuzumab ozogamicin in relapsed B-cell acute lymphoblastic leukemia. Eur J Haematol. 2017 May;98(5):425-434. doi: 10.1111/ejh.12862. Epub 2017 Mar 9. [Article]
- Yurkiewicz IR, Muffly L, Liedtke M: Inotuzumab ozogamicin: a CD22 mAb-drug conjugate for adult relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Drug Des Devel Ther. 2018 Jul 24;12:2293-2300. doi: 10.2147/DDDT.S150317. eCollection 2018. [Article]
- EMA Approved Drug Products: BESPONSA (inotuzumab ozogamicin) Intravenous Injection [Link]
- FDA Approved Drug Products: BESPONSA (inotuzumab ozogamicin) for injection, for intravenous use [Link]
- External Links
- PubChem Substance
- 347910296
- 1942950
- Wikipedia
- Inotuzumab_ozogamicin
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Active Not Recruiting Not Available Hematologic Maligmancy 1 somestatus stop reason just information to hide Not Available Completed Not Available Adult Relapsed/Refractory B Cell Acute Lymphoblastic Leukemia 1 somestatus stop reason just information to hide Not Available Completed Not Available Precursor Cell Lymphoblastic Leukemia-Lymphoma 1 somestatus stop reason just information to hide Not Available Not Yet Recruiting Treatment Bone Marrow Transplant (BMT) / Minimal Residual Disease / Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL) 1 somestatus stop reason just information to hide 4 Active Not Recruiting Treatment Acute Lymphoblastic Leukemia (ALL) 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, powder, for solution Intravenous 1 mg Injection, powder, for solution Intravenous; Parenteral 1 MG Injection, powder, lyophilized, for solution Intravenous 0.25 mg/1mL Powder, for solution Intravenous 0.9 mg / vial Injection, powder, for solution 1 mg Powder, for solution Intravenous 1 mg - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- AntibodyRegulator
- General Function
- Most highly expressed siglec (sialic acid-binding immunoglobulin-like lectin) on B-cells that plays a role in various aspects of B-cell biology including differentiation, antigen presentation, and trafficking to bone marrow (PubMed:8627166, PubMed:34330755). Binds to alpha 2,6-linked sialic acid residues of surface molecules such as CD22 itself, CD45 and IgM in a cis configuration. Can also bind to ligands on other cells as an adhesion molecule in a trans configuration (PubMed:20172905). Acts as an inhibitory coreceptor on the surface of B-cells and inhibits B-cell receptor induced signaling, characterized by inhibition of the calcium mobilization and cellular activation. Mechanistically, the immunoreceptor tyrosine-based inhibitory motif domain is phosphorylated by the Src kinase LYN, which in turn leads to the recruitment of the protein tyrosine phosphatase 1/PTPN6, leading to the negative regulation of BCR signaling (PubMed:8627166). If this negative signaling from is of sufficient strength, apoptosis of the B-cell can be induced (PubMed:20516366)
- Specific Function
- carbohydrate binding
- Gene Name
- CD22
- Uniprot ID
- P20273
- Uniprot Name
- B-cell receptor CD22
- Molecular Weight
- 95347.07 Da
References
- Thota S, Advani A: Inotuzumab ozogamicin in relapsed B-cell acute lymphoblastic leukemia. Eur J Haematol. 2017 May;98(5):425-434. doi: 10.1111/ejh.12862. Epub 2017 Mar 9. [Article]
- Kyriakidis I, Vasileiou E, Rossig C, Roilides E, Groll AH, Tragiannidis A: Invasive Fungal Diseases in Children with Hematological Malignancies Treated with Therapies That Target Cell Surface Antigens: Monoclonal Antibodies, Immune Checkpoint Inhibitors and CAR T-Cell Therapies. J Fungi (Basel). 2021 Mar 5;7(3). pii: jof7030186. doi: 10.3390/jof7030186. [Article]
- FDA Approved Drug Products: BESPONSA (inotuzumab ozogamicin) for injection, for intravenous use [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- Curator comments
- N-acetyl-gamma-calicheamicin dimethylhydrazide, a component of inotuzumab ozogamicin, is a substrate of P-glycoprotein (P-gp).
- General Function
- Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- ATP-dependent translocase ABCB1
- Molecular Weight
- 141477.255 Da
References
Drug created at November 18, 2007 18:28 / Updated at May 18, 2024 15:37