NAV

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 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
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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

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofRefractory cd22-positive b-cell precursor acute lymphoblastic leukemia (all)•••••••••••••••••
Treatment ofRefractory cd22-positive b-cell precursor acute lymphoblastic leukemia (all)••••••••••••
Treatment ofRelapsed cd22-positive b-cell precursor acute lymphoblastic leukemia (all)•••••••••••••••••
Treatment ofRelapsed cd22-positive b-cell precursor acute lymphoblastic leukemia (all)••••••••••••
Associated Therapies
Contraindications & Blackbox Warnings
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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

TargetActionsOrganism
AB-cell receptor CD22
antibody
regulator
Humans
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.
DrugInteraction
Integrate drug-drug
interactions in your software
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Inotuzumab ozogamicin.
AcebutololThe risk or severity of QTc prolongation can be increased when Acebutolol is combined with Inotuzumab ozogamicin.
AcrivastineThe risk or severity of QTc prolongation can be increased when Acrivastine is combined with Inotuzumab ozogamicin.
AdagrasibThe risk or severity of QTc prolongation can be increased when Adagrasib is combined with Inotuzumab ozogamicin.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Inotuzumab ozogamicin.
Food Interactions
No interactions found.

Products

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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
BesponsaInjection, powder, for solution1 mgIntravenousPfizer Europe Ma Eeig2020-12-23Not applicableEU flag
BesponsaPowder, for solution0.9 mg / vialIntravenousPfizer Canada Ulc2018-05-03Not applicableCanada flag

Categories

ATC Codes
L01FB01 — 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
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
P93RUU11P7
CAS number
635715-01-4

References

General References
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. 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]
  7. EMA Approved Drug Products: BESPONSA (inotuzumab ozogamicin) Intravenous Injection [Link]
  8. FDA Approved Drug Products: BESPONSA (inotuzumab ozogamicin) for injection, for intravenous use [Link]
PubChem Substance
347910296
RxNav
1942950
Wikipedia
Inotuzumab_ozogamicin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentAcute Lymphoblastic Leukemia (ALL)1
4CompletedTreatmentAcute Lymphoblastic Leukemia (ALL) / Leukemias / Precursor B-Cell Lymphoblastic Leukemia-Lymphoma1
3CompletedTreatmentAcute Lymphoblastic Leukemia (ALL)1
3RecruitingTreatmentAcute Lymphoblastic Leukemia (ALL)1
3RecruitingTreatmentB-cell Acute Lymphoblastic Leukemia / Central Nervous System Leukemia / Lymphoblastic B-Cell Lymphoma / Mixed Phenotype Acute Leukemia (MPAL) / Testicular Leukemia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous1 mg
Injection, powder, for solutionIntravenous; Parenteral1 MG
Injection, powder, lyophilized, for solutionIntravenous0.25 mg/1mL
Powder, for solutionIntravenous0.9 mg / vial
Injection, powder, for solution1 mg
Powder, for solutionIntravenous1 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Targets

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Details1. B-cell receptor CD22
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antibody
Regulator
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. [Article]
  2. 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]
  3. FDA Approved Drug Products: BESPONSA (inotuzumab ozogamicin) for injection, for intravenous use [Link]

Transporters

Details1. P-glycoprotein 1
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
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. EMA Approved Drug Products: BESPONSA (inotuzumab ozogamicin) Intravenous Injection [Link]
  2. FDA Approved Drug Products: BESPONSA (inotuzumab ozogamicin) for injection, for intravenous use [Link]

Drug created at November 18, 2007 18:28 / Updated at April 30, 2024 13:27