Gemtuzumab Ozogamicin Overview

Introduction of Gemtuzumab Ozogamicin

Gemtuzumab ozogamicin (Mylotarg®; Pfizer/Wyeth-Ayerst Laboratories) is a humanized IgG4 anti-CD33 monoclonal antibody (hP67.6) conjugated to N-acetyl-γ calicheamicin dimethyl hydrazide (NAc-gamma calicheamicin DMH), a derivative of calicheamicin. The constant region and framework regions of the hP67.6 antibody contain human sequences, whereas the complementarity-determining regions (CDRs) are derived from a murine antibody (p67.6) that binds CD33. Calicheamicin is a naturally-occurring hydrophobic enediyne antibiotic that was isolated from the actinomycete Micromonospora echinospora calichensis. Conjugation with the antibody is obtained by covalent linkage (condensation) of a bifunctional linker, 4-(4-acetylphenoxy)butanoic acid (AcBut linker), which allows the most favourable balance between hydrolytic stability in physiological buffers (pH 7.4) and efficient drug release at the pH of lysosomes ( ∼ 4). Gemtuzumab ozogamicin was created in a collaboration between Celltech and Wyeth that began in 1991. In the United States (US), it was approved under an accelerated-approval process by the Food and Drug Administration (FDA) in 2000 for use in patients over the age of 60 with relapsed acute myelogenous leukemia (AML); or those who are not considered candidates for standard chemotherapy. The accelerated approval was based on the surrogate endpoint of response rate. It was the first antibody-drug conjugate to be approved. Within the first year after approval, the FDA required a black box warning be added to Gemtuzumab packaging. The drug was noted to increase the risk of veno-occlusive disease in the absence of bone marrow transplantation. In June 2010, Pfizer withdrew Mylotarg from the market at the request of the US FDA. However, some other regulatory authorities did not agree with the FDA decision, with Japan's Pharmaceuticals and Medical Devices Agency stating in 2011 that the "risk-benefit balance of gemtuzumab ozogamicin has not changed from its state at the time of approval". In early 2017 Pfizer reapplied for US and EU approval, based on a meta-analysis of prior trials and results of the ALFA-0701 clinical trial, an open-label Phase III trial in 280 older people with AML.

Mechanism of Action of Gemtuzumab Ozogamicin

The CD33 antigen is a sialic acid-dependent adhesion protein that is specific for myeloid cells. CD33 is expressed in approximately 90% of AML cases, as defined by the presence of the antigen on > 20% of the leukemic blasts but not on normal CD34+ pluripotent hematopoietic stem cells or non-hematopoietic tissues. Gemtuzumab ozogamicin consists of a humanized anti-CD33 antibody, produced from a mammalian myeloma cell line, covalently linked to a semisynthetic derivative of a potent cytotoxic enediyne antibiotic called calicheamicin. Gemtuzumab ozogamicin targets CD33-expressing cells. Binding to the antigen is followed by endocytosis. The covalent link is cleaved inside lysosomes, allowing calicheamicin release. Calicheamicin binds to DNA within the minor groove and causes double-strand breaks and ultimately, cell apoptosis.

Fig.1 Mechanism of action of gemtuzumab ozogamicin

Table 1. Clinical Projects of Gemtuzumab Ozogamicin*

Table 2. Approved Drugs of Gemtuzumab Ozogamicin**

INN (trade name)	Therapeutic area	Dose	Strength	Route	Company	Marketing start	Market
Mylotarg	CD33-positive acute myeloid leukemia (AML)	Powder for solution	4.5 mg	Intravenous infusion	Wyeth Pharms Inc	September 4, 2018
Keytruda	Leukemia, Myeloid, Acute	Powder for solution	5 mg	Intravenous infusion	Pfizer Europe MA EEIG	April 18, 2018
Keytruda	CD33-positive acute myeloid leukemia (AML)	Powder for solution	5 mg	Intravenous infusion	Pfizer Japan Inc	June 6, 2018

What We Provide

Therapeutic Antibody

Gemtuzumab ozogamicin

We provide high-quality Gemtuzumab 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=Gemtuzumab+Ozogamicin

** Information presented in the table were collected from the following websites:
https://www.ema.europa.eu/en/medicines/human/EPAR/mylotarg-0
http://www.pmda.go.jp/PmdaSearch/iyakuDetail/GeneralList/4239400D1
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=761060

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