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

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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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Associated Conditions

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		••••••••••••	•••••

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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	antibody regulator	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 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

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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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abciximab	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

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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
Besponsa	Injection, powder, lyophilized, for solution	0.25 mg/1mL	Intravenous	Wyeth Pharmaceuticals Llc, a Subsidiary of Pfizer Inc.	2017-08-18	Not applicable
Besponsa	Injection, powder, for solution	1 mg	Intravenous	Pfizer Europe Ma Eeig	2020-12-23	Not applicable

Categories

ATC Codes

L01FB01 — Inotuzumab ozogamicin

• L01FB — CD22 (Clusters of Differentiation 22) inhibitors
• L01F — MONOCLONAL ANTIBODIES AND ANTIBODY DRUG CONJUGATES
• L01 — ANTINEOPLASTIC AGENTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

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

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. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
6. 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]
7. European Medicines Agency (EMA): BESPONSA Summary of Product Characteristics [Link]

External Links

PubChem Substance

347910296

RxNav

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

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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]

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Drug created at November 18, 2007 18:28 / Updated at June 03, 2022 07:24