Inotuzumab ozogamicin
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 using linker and cytotoxic drug technology similar to that developed for the ground-breaking treatment Mylotarg (Gemtuzumab ozogamicin), which was approved by the US FDA in 2000 for the treatment of acute myeloid leukaemia. Inotuzumab ozogamicin consists of a recombinant humanised IgG4 kappa CD22-targeting monoclonal antibody covalently attached to calicheamicin derivative, N-acetyl-gamma-calicheamicin dimethylhydrazide, which is a potent DNA-binding cytotoxic agent 4. Developed by Pfizer and UCB, inotuzumab ozogamicin was granted approval by EU in June 2017 followed by FDA on August 17th, 2017 for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). ALL is a rapidly progressing cancer of the bone marrow that is associated with high mortality rates and low therapeutic response from standard chemotherapies in relasping conditions. In a randomized trial, inotuzumab ozogamicin displayed higher percentages of patients undergoing longer periods of complete remission with no evidence of disease in comparison to patients receiving alternative chemotherapy 5.
- Type
- Biotech
- Groups
- Approved, Investigational
- Biologic Classification
- Protein Based Therapies
Monoclonal antibody (mAb) - Protein Structure
- Protein Chemical Formula
- Not Available
- Protein Average Weight
- Not Available
- Sequences
- Not Available
- Synonyms
- Inotuzumab ozogamicin
- External IDs
- CMC 544
- CMC-544
- PF-05208773
- WAY-207294
Pharmacology
- Indication
Indicated as monotherapy for the treatment of adults with relapsed or refractory CD22-positive B cell precursor acute lymphoblastic leukaemia (ALL).
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form 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
Inotuzumab ozogamicin is an antineoplastic agent that targets CD22 antigen expressed on immature B-cell lymphocytes and blocks further growth of tumor cells. The drug aims to restore normal blood counts and achieve complete remission from the disease. QT interval prolongation was observed in patients receiving inotuzumab ozogamicin.
- Mechanism of action
Inotuzumab ozogamicin is comprised of cytotoxic antibiotic N-acetyl-gamma-calicheamicin dimethylhydrazide attached to a humanized monoclonal IgG4 antibody via 4-(4 acetylphenoxy) butanoic acid (acetyl butyrate) linker. The drug exerts a potent cytotoxic effect against CD22+ B-cell lymphoma when the antibody binds to the CD22 receptor on the surface of B cells . The drug-CD22 complex is rapidly internalized into the cell, forming an endosome which subsequently fuses with lysosomes. N-acetyl-gamma-calicheamicin dimethylhydrazide is then intracellularly released into the acidic environment. N-acetyl-gamma-calicheamicin dimethylhydrazide is a calicheamicin derivative, which is naturally produced by the bacterium Micromonospora echinospora, and is toxic to the body when not bound to the antibody. It mediates apoptosis of the cell by binding to the minor groove of DNA in a sequence-specific manner and undergoing a structural change to generate diradicals 6. These changes abstract hydrogen ions from the phosphodiester bonds of double-stranded DNA, resulting in breaks and cell apoptosis 1,2,4.
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. The steady state exposure of the drug is reached by Cycle 4. The mean (SD) maximum serum concentration (Cmax) of inotuzumab ozogamicin was 308 ng/mL (362) with patients receving the recommended dose of 1.8 mg/m^2/cycle 7.
- Volume of distribution
The total volume of distribution of inotuzumab ozogamicin is approximately 12L 7.
- Protein binding
In vitro studies show the binding of the N-acetyl-gamma-calicheamicin dimethylhydrazide to human plasma proteins to be approximately 97% 7.
- Metabolism
N-acetyl-gamma-calicheamicin dimethylhydrazide primarily undergoes nonenzymatic reduction in vitro. The metabolism of N-acetyl-gamma-calicheamicin dimethylhydrazide in human serum is not clearly understood as the level of the drug is below the limit of quantification of 50 pg/mL 7. The antibody portion of the drug is thought to undergo proteolytic degradation into amino acids then recycled into other proteins 3.
- Route of elimination
The drug is disposited in the body after administration.
- Half-life
The elimination half life at the end of Cycle 4 of administration is approximately 12.3 days in a 2-compartment model 7.
- Clearance
The clearance of inotuzumab ozogamicin at steady state is 0.0333 L/h 7.
- Adverse Effects
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- Toxicity
Inotuzumab ozogamicin was shown to be clastogenic in vivo in the bone marrow of male mice but was not mutagenic in an* in vitro* bacterial reverse mutation (Ames) assay. In rat toxicity studies, rats developed oval cell hyperplasia, altered hepatocellular foci, and hepatocellular adenomas however the carcinogenic potential of inotuzumab ozogamicin on humans is undetermined. Based on reproductive toxicity studies involving female rats and non-clinical studies, inotuzumab ozogamicin has the potential to impair reproductive function and fertility in men and women 7.
- 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 softwareAbciximab The risk or severity of adverse effects can be increased when Abciximab is combined with Inotuzumab ozogamicin. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Inotuzumab ozogamicin. Abrocitinib The serum concentration of Inotuzumab ozogamicin can be increased when it is combined with Abrocitinib. Adagrasib The serum concentration of Inotuzumab ozogamicin can be increased when it is combined with Adagrasib. 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 Powder, for solution 0.9 mg / vial Intravenous Pfizer Canada Ulc 2018-05-03 Not applicable Canada 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
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
- 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, Goad ME, Dougher MM, Boghaert ER, Kunz A, Hamann PR, Damle NK: Potent and specific antitumor efficacy of CMC-544, a CD22-targeted immunoconjugate of calicheamicin, against systemically disseminated B-cell lymphoma. Clin Cancer Res. 2004 Dec 15;10(24):8620-9. [Article]
- 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]
- European Medicines Agency (EMA): BESPONSA Summary of Product Characteristics [Link]
- External Links
- PubChem Substance
- 347910296
- 1942950
- Wikipedia
- Inotuzumab_ozogamicin
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 Active Not Recruiting Treatment Acute Lymphoblastic Leukaemias (ALL) 1 4 Completed Treatment Acute Lymphoblastic Leukaemias (ALL) / Leukemias / Precursor B-Cell Lymphoblastic Leukemia-Lymphoma 1 3 Completed Treatment Acute Lymphoblastic Leukaemias (ALL) 1 3 Recruiting Treatment Acute Lymphoblastic Leukaemias (ALL) 1 3 Recruiting Treatment B-cell Acute Lymphoblastic Leukemia / Central Nervous System Leukemia / Lymphoblastic B-Cell Lymphoma / Mixed Phenotype Acute Leukemia (MPAL) / Testicular Leukemia 1
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
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- AntibodyRegulator
- General Function
- Carbohydrate binding
- Specific Function
- Mediates B-cell B-cell interactions. May be involved in the localization of B-cells in lymphoid tissues. Binds sialylated glycoproteins; one of which is CD45. Preferentially binds to alpha-2,6-link...
- 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]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- Multidrug resistance protein 1
- Molecular Weight
- 141477.255 Da
References
- European Medicines Agency (EMA): BESPONSA Summary of Product Characteristics [Link]
Drug created at November 18, 2007 18:28 / Updated at June 03, 2022 07:24