Identification

Name
Inotuzumab ozogamicin
Accession Number
DB05889
Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
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].

Protein structure
Db05889
Protein chemical formula
Not Available
Protein average weight
Not Available
Sequences
Not Available
Synonyms
  • CMC 544
  • WAY-207294
External IDs
CMC-544 / PF-05208773 / WAY-207294
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
BesponsaInjection, powder, lyophilized, for solution.25 mg/mLIntravenousWyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc.2017-08-18Not applicableUs
Categories
UNII
P93RUU11P7
CAS number
635715-01-4

Pharmacology

Indication

Indicated as monotherapy for the treatment of adults with relapsed or refractory CD22-positive B cell precursor acute lymphoblastic leukaemia (ALL).

Structured Indications
Not Available
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
Human
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].

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
DrugInteractionDrug group
BCG vaccineThe therapeutic efficacy of BCG vaccine can be decreased when used in combination with Inotuzumab ozogamicin.Investigational
BelimumabThe risk or severity of adverse effects can be increased when Inotuzumab ozogamicin is combined with Belimumab.Approved
Clostridium tetani toxoid antigen (formaldehyde inactivated)The therapeutic efficacy of Clostridium tetani toxoid antigen (formaldehyde inactivated) can be decreased when used in combination with Inotuzumab ozogamicin.Approved
Corynebacterium diphtheriae toxoid antigen (formaldehyde inactivated)The therapeutic efficacy of Corynebacterium diphtheriae toxoid antigen (formaldehyde inactivated) can be decreased when used in combination with Inotuzumab ozogamicin.Approved
G17DTThe therapeutic efficacy of G17DT can be decreased when used in combination with Inotuzumab ozogamicin.Investigational
GI-5005The therapeutic efficacy of GI-5005 can be decreased when used in combination with Inotuzumab ozogamicin.Investigational
Hepatitis A VaccineThe therapeutic efficacy of Hepatitis A Vaccine can be decreased when used in combination with Inotuzumab ozogamicin.Approved
Hepatitis B Vaccine (Recombinant)The therapeutic efficacy of Hepatitis B Vaccine (Recombinant) can be decreased when used in combination with Inotuzumab ozogamicin.Approved, Withdrawn
INGN 201The therapeutic efficacy of INGN 201 can be decreased when used in combination with Inotuzumab ozogamicin.Investigational
INGN 225The therapeutic efficacy of INGN 225 can be decreased when used in combination with Inotuzumab ozogamicin.Investigational
LumacaftorThe serum concentration of Inotuzumab ozogamicin can be decreased when it is combined with Lumacaftor.Approved
Rabies virus inactivated antigen, AThe therapeutic efficacy of Rabies virus inactivated antigen, A can be decreased when used in combination with Inotuzumab ozogamicin.Approved
RanolazineThe serum concentration of Inotuzumab ozogamicin can be increased when it is combined with Ranolazine.Approved, Investigational
RindopepimutThe therapeutic efficacy of Rindopepimut can be decreased when used in combination with Inotuzumab ozogamicin.Investigational
Rotavirus VaccineThe therapeutic efficacy of Rotavirus Vaccine can be decreased when used in combination with Inotuzumab ozogamicin.Approved
Rubella virus vaccineThe therapeutic efficacy of Rubella virus vaccine can be decreased when used in combination with Inotuzumab ozogamicin.Approved
Salmonella typhi ty21a live antigenThe therapeutic efficacy of Salmonella typhi ty21a live antigen can be decreased when used in combination with Inotuzumab ozogamicin.Approved
SRP 299The therapeutic efficacy of SRP 299 can be decreased when used in combination with Inotuzumab ozogamicin.Investigational
TecemotideThe therapeutic efficacy of Tecemotide can be decreased when used in combination with Inotuzumab ozogamicin.Investigational
TG4010The therapeutic efficacy of TG4010 can be decreased when used in combination with Inotuzumab ozogamicin.Investigational
Varicella Zoster Vaccine (Live/Attenuated)The therapeutic efficacy of Zoster vaccine can be decreased when used in combination with Inotuzumab ozogamicin.Approved
Yellow fever vaccineThe therapeutic efficacy of Yellow fever vaccine can be decreased when used in combination with Inotuzumab ozogamicin.Approved
Food Interactions
Not Available

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]
External Links
PubChem Substance
347910296
Wikipedia
Inotuzumab_ozogamicin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL)1
1CompletedTreatmentLymphoma, B-Cell4
1CompletedTreatmentRefractory Follicular Lymphoma1
1RecruitingTreatmentAcute Leukemias of Ambiguous Lineage / B-cell Adult Acute Lymphoblastic Leukemia / Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia / Recurrent Adult Acute Lymphoblastic Leukemia / Recurrent Adult Burkitt Lymphoma1
1, 2Active Not RecruitingTreatmentAcute Lymphocytic Leukemia (ALL)1
1, 2CompletedTreatmentLymphoma, B-Cell1
1, 2RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / Leukemias1
1, 2RecruitingTreatmentCD22-positive Acute Lymphoblastic Leukemia / Cluster of Differentiation Antigen (CD22)-Positive Acute Lymphoblastic Leukemia1
1, 2RecruitingTreatmentLeukemias1
1, 2RecruitingTreatmentLeukemias / Malignant Lymphomas1
2CompletedTreatmentLymphoma, B-Cell1
2CompletedTreatmentMalignant Lymphomas1
2Not Yet RecruitingTreatmentAcute Lymphocytic Leukemia (ALL)1
2RecruitingTreatmentChildhood B Acute Lymphoblastic Leukemia / Recurrent Childhood Acute Lymphoblastic Leukemia / Refractory Childhood Acute Lymphoblastic Leukemia1
2RecruitingTreatmentLymphoma, Large B-Cell, Diffuse (DLBCL)1
3Active Not RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL)1
3RecruitingTreatmentB Acute Lymphoblastic Leukemia1
3TerminatedHealth Services ResearchFollicular Lymphoma (FL)1
3TerminatedTreatmentNon-Hodgkin's Lymphoma (NHL)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous.25 mg/mL
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

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

Targets

Kind
Protein
Organism
Human
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
Human
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 November 06, 2017 06:45