Inotuzumab ozogamicin

Identification

Name
Inotuzumab ozogamicin
Accession Number
DB05889
Description

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
Db05889
Protein Chemical Formula
Not Available
Protein Average Weight
Not Available
Sequences
Not Available
Synonyms
Not Available
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).

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
Learn More
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 [A20354]. These changes abstract hydrogen ions from the phosphodiester bonds of double-stranded DNA, resulting in breaks and cell apoptosis 1,2,4.

TargetActionsOrganism
AB-cell receptor CD22
antibody
Humans
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 6.

Volume of distribution

The total volume of distribution of inotuzumab ozogamicin is approximately 12L 6.

Protein binding

In vitro studies show the binding of the N-acetyl-gamma-calicheamicin dimethylhydrazide to human plasma proteins to be approximately 97% 6.

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 6. 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 6.

Clearance

The clearance of inotuzumab ozogamicin at steady state is 0.0333 L/h 6.

Adverse Effects
Learn about our commercial Adverse Effects data.
Learn More
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 6.

Affected organisms
  • Humans and other mammals
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
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Inotuzumab ozogamicin.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Inotuzumab ozogamicin.
AfatinibThe serum concentration of Inotuzumab ozogamicin can be increased when it is combined with Afatinib.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Inotuzumab ozogamicin.
AlirocumabThe risk or severity of adverse effects can be increased when Inotuzumab ozogamicin is combined with Alirocumab.
AmbrisentanThe serum concentration of Ambrisentan can be increased when it is combined with Inotuzumab ozogamicin.
AmiodaroneThe serum concentration of Inotuzumab ozogamicin can be increased when it is combined with Amiodarone.
Anthrax immune globulin humanThe risk or severity of adverse effects can be increased when Inotuzumab ozogamicin is combined with Anthrax immune globulin human.
Antilymphocyte immunoglobulin (horse)The risk or severity of adverse effects can be increased when Inotuzumab ozogamicin is combined with Antilymphocyte immunoglobulin (horse).
Antithymocyte immunoglobulin (rabbit)The risk or severity of adverse effects can be increased when Antithymocyte immunoglobulin (rabbit) is combined with Inotuzumab ozogamicin.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

    Learn more
  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

    Learn more
  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

    Learn more
  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

    Learn more
Food Interactions
Not Available

Products

Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
BesponsaInjection, powder, lyophilized, for solution0.25 mg/1mLIntravenousWyeth Pharmaceuticals Llc, a Subsidiary of Pfizer Inc.2017-08-18Not applicableUS flag
BesponsaPowder, for solution0.9 mgIntravenousPfizer Canada Ulc2018-05-03Not applicableCanada flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

    Learn more
  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

    Learn more

Categories

ATC Codes
L01XC26 — Inotuzumab ozogamicin
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

Chemical Identifiers

UNII
P93RUU11P7
CAS number
635715-01-4

References

General References
  1. 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. [PubMed:15623646]
  2. 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. [PubMed:17657218]
  3. 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. [PubMed:25048520]
  4. 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. [PubMed:26425338]
  5. 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. [PubMed:27292104]
  6. European Medicines Agency (EMA): BESPONSA Summary of Product Characteristics [Link]
PubChem Substance
347910296
RxNav
1942950
Wikipedia
Inotuzumab_ozogamicin
AHFS Codes
  • 10:00.00 — Antineoplastic Agents

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / Leukemias / Precursor B-Cell Lymphoblastic Leukemia-Lymphoma1
3CompletedTreatmentAcute Lymphoblastic Leukaemias (ALL)1
3RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL)1
3RecruitingTreatmentB Acute Lymphoblastic Leukemia1
3RecruitingTreatmentB Acute Lymphoblastic Leukemia / B Lymphoblastic Lymphoma / Central Nervous System Leukemia / Mixed Phenotype Acute Leukemia (MPAL) / Testicular Leukemia1
3TerminatedHealth Services ResearchFollicular Lymphoma (FL)1
3TerminatedTreatmentNon-Hodgkin's Lymphoma (NHL)1
3WithdrawnTreatmentAcute Lymphoblastic Leukaemias (ALL)1
2Active Not RecruitingTreatmentDiffuse Large B-Cell Lymphoma (DLBCL)1
2Active Not RecruitingTreatmentRecurrent B Acute Lymphoblastic Leukemia / Recurrent B Lymphoblastic Lymphoma / Refractory B Acute Lymphoblastic Leukemia / Refractory B Lymphoblastic Lymphoma1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous; Parenteral1 MG
Injection, powder, lyophilized, for solutionIntravenous0.25 mg/1mL
Powder, for solutionIntravenous0.9 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antibody
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
  1. 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. [PubMed:28152223]

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
  1. European Medicines Agency (EMA): BESPONSA Summary of Product Characteristics [Link]

Drug created on November 18, 2007 11:28 / Updated on October 25, 2020 09:16

Logo pink
Are you a
new drug developer?
Contact us to learn more about our customized products and solutions.
Logo pink
Stay in the know!
As part of our commitment to providing the most up-to-date drug information, we will be releasing #DrugBankUpdates with our newly added curated drug pages.
#DrugBankUpdates