Inotuzumab Ozogamicin Overview

Introduction of Inotuzumab Ozogamicin

Inotuzumab ozogamicin (CMC-544) is an antibody-drug conjugate (ADC) that consists of a derivative of calicheamicin (a potent DNA-binding cytotoxic agent) attached to an engineered humanized monoclonal immunoglobulin G4 (IgG4) antibody targeting CD22. CD22 is a member of a homologous family of sialic-acid-binding immunoglobulin-like lectins (siglecs), which comprise a group of receptors that are restrictedly expressed in immune cells. Siglecs are endocytic receptors where cytotoxic agents conjugated to an antibody can bind and effectively carried into the cell without shedding into the extracellular environment. The therapeutic effect of inotuzumab ozogamicin has initially been shown in non-Hodgkin lymphoma (NHL). This drug was discovered by scientists collaborating at Celltech and Wyeth, and it was developed by Pfizer which had acquired Wyeth. In 2017 inotuzumab ozogamicin was approved by the European Medicines Agency and the U.S. Food and Drug Administration (FDA) for the treatment of adults with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL) in 2017 under the trade name Besponsa.

Mechanism of Action of Inotuzumab Ozogamicin

Inotuzumab ozogamicin consists of a semisynthetic derivative of N-acetyl ɣ-calicheamicin 1, 2-dimethyl hydrazine dichloride (NAc ɣ-calicheamicin DMH), a potent DNA-binding cytotoxic antibiotic, attached to a humanized monoclonal IgG4 antibody, G544, directed against the CD22 antigen present on B cells in all patients with mature B-ALL and most patients (>90%) with precursor B-ALL. Anti-CD22 monoclonal antibody (mAb) without conjugated cytotoxic drug has shown to have no antitumor activity in preclinical models; instead conjugation with cytotoxic agent provided potent dose-depending cellular damage. IgG4 antibodies alone poorly fix complement and therefore cannot cause apoptosis via complement-mediated and antibody-dependent cytotoxicity. Calicheamicin is natural product of Micromon-ospora echinospora and considered to be intolerantly toxic when not bound to the antibody. Calicheamicin is linked to the antibody through 4-(4-acetylphenoxy) butanoic acid (acetyl butyrate), which provides stability in physiologic pH and successful calicheamicin release inside the acidic environment of the lysosomes. Inotuzumab ozogamicin binds to the CD22 receptor on the surface of B cells and the CD22 receptor-inotuzumab ozogamicin complex is internalized forming an endosome. Subsequently, the CD22 receptor-inotuzumab ozogamicin complex containing endosome fuses with lysosomes. This is followed by intracellular release of calicheamicin. Calicheamicin binds to the minor groove of DNA in a sequence specific manner and breaks double-stranded DNA, resulting in cell death.

Fig.1 Mechanism of action of inotuzumab ozogamicin

Table 1. Clinical Projects of Inotuzumab ozogamicin*

Table 2. Approved Drugs of Inotuzumab ozogamicin**

INN (trade name)	Therapeutic area	Dose	Strength	Route	Company	Marketing start	Market
Besponsa	Relapsed or refractory B-cell precursor acute lymphoblastic leukemia	Powder for injection	0.9 mg / vial	Intravenous infusion	Wyeth Pharms Inc.	August 17, 2017
Besponsa	Precursor Cell Lymphoblastic Leukemia-Lymphoma	Powder for injection	1 mg / vial	Intravenous infusion	Pfizer Limited	June 29, 2017
Besponsa	Relapsed or refractory B-cell precursor acute lymphoblastic leukemia	Powder for injection	1 mg / vial	Intravenous infusion	Pfizer Japan Inc.	January 19, 2018
Besponsa	Relapsed or refractory B-cell precursor acute lymphoblastic leukemia	Powder for injection	0.9 mg / vial	Intravenous infusion	Pfizer Canada Inc.	May 3, 2018
Besponsa	Relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia	Powder for injection	1 mg / vial	Intravenous infusion	Pfizer Australia Pty Ltd	May 17, 2018

What We Provide

Therapeutic Antibody

Inotuzumab Ozogamicin

We provide high-quality Inotuzumab Ozogamicin for use in WB, FC, IP, ELISA, Neut, FuncS, IF and most other immunological methods. For lab research use only, not for diagnostic, therapeutic or any in vivo human use.

Reference
* The table was excerpted from the following website
https://clinicaltrials.gov/ct2/results?cond=&term=Inotuzumab+ozogamicin

** Information presented in the table was collected from the following websites:
http://www.pmda.go.jp/PmdaSearch/iyakuDetail/GeneralList/4239401D1
https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=96383
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=761040
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004119/human_med_002109.jsp
http://search.tga.gov.au/s/search.html?collection=tga-artg&profile=record&meta_i=288135

For research use only. Not intended for any clinical use.