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Monoclonal Antibody Mediated Treatment in Acute Myeloid Leukemia
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Ch. Michel Zwaan, Marry M. van den Heuvel-Eibrink
The most promising results have been obtained with GO, Mylotarg®, a humanized anti-CD33 monoclonal antibody linked to calicheamicin, which is a potent enidyne antileukemic antibiotic. Calicheamicin dissociates from the antibody-calicheamicin complex after internalization, binds to the minor groove of DNA, and results in DNA-double strand breaks (Fig. 1). The results of the various phase I/II studies in adults are summarized in Table 2, and some are discussed in more detail below.
Iodine is needed to maintain health
Published in Tatsuo Kaiho, Iodine Made Simple, 2017
In 1981, calicheamicin was isolated from bacteria existing in caliches (limestone) in Kerrville, Texas. The cytotoxicity of calicheamicin is 3000 times stronger than general anticancer drugs, and was first marketed in 2000 as Gemtuzumab ozogamicin, a molecular target drug for nonsolid carcinoma acute myeloid leukemia. The carbohydrate chain in calicheamicin recognizes and bonds with the DNA (deoxyribonucleic acid) sequence, and the core of the enediyne generates biradicals which cause DNA cleavage. Currently, the iodine atoms are thought to determine positioning of the attack site.
Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Calicheamicin (Figure 7.17 A) is a member of the enediyne class of antitumor antibiotics (calicheamicin γ1 being the most notable) originally isolated in the mid-1980s from the bacterium Micromonospora echinospora found in the chalky soil (or “calichi pits”, see Figure 7.17 B) in Kerrville, Texas (USA). The sample was collected by a scientist working for Lederle Labs. Caliche is a sedimentary rock, a hardened natural cement of calcium carbonate binding other materials such as gravel, sand, clay, and silt which occurs worldwide, generally in arid or semi-arid regions. Calicheamicin γ1 and the related enediyne esperamicin are two of the most cytotoxic agents known, and are discussed in more detail in Chapter 5. A. Structure of calicheamicin; B. Caliche clay found in central Texas (USA) of the type that the calicheamicin-producing microorganism (Micromonospora echinospora ssp calichensis) was first isolated from (Figure from Wikipedia, “Caliche-5731” by Loadmaster (David R. Tribble), under the Creative Commons Attribution-Share Alike 3.0 Unported license (https://creativecommons.org/licenses/by-sa/3.0/deed.en)).
Treatment and outcome of Philadelphia chromosome-positive acute lymphoblastic leukemia in adults after relapse
Published in Expert Review of Anticancer Therapy, 2020
Marie Balsat, Victoria Cacheux, Martin Carre, Emmanuelle Tavernier-Tardy, Xavier Thomas
CD22 is a 135-kDa sialoglycoprotein that mediates intercellular interactions for sialic-acid bearing ligands and modulates antigen receptor signaling and B-cell activation. CD22 is an important B cell-restricted surface antigen that is expressed in 96% of B cell-lineage ALL [103]. It is rapidly internalized on binding to anti-CD22 making it an attractive target for targeted therapy with chemotherapeutic conjugates. Following the development of gemtuzumab ozogamicin, an anti-CD33 antibody-drug conjugate, in acute myeloid leukemia, inotuzumab ozogamicin, an anti-CD22 antibody-drug conjugate, was developed. Inotuzumab ozogamicin is a humanized MoAb against CD22 conjugated via a bi-functional linker to a potent cytotoxic agent calicheamicin derived from Micromonospora echinospora, which induces DNA double-strand breaks and apoptosis independent of cell cycle progression [104]. Upon binding to CD22 receptors, inotuzumab is rapidly internalized, trafficked through lysosomes leading to hydrolysis of inactive calicheamicin. Calicheamicin is then reduced to its active form by intracellular glutathione. In the nucleus, active calicheamicin binds to DNA and generates free radicals leading to DNA double-strand breaks and cellular apoptosis (Figure 2).
Gemtuzumab ozogamicin for the treatment of acute myeloid leukemia
Published in Expert Review of Clinical Pharmacology, 2018
GO is an antibody-drug conjugate (ADC) consisting of an antibody directed against human CD33 (gemtuzumab) linked to a cytotoxic component (ozogamicin). The transmembrane surface receptor, CD33, is an attractive target for AML as it is nearly ubiquitously expressed on hematopoietic cells of myeloid lineage and myeloblasts in >80% of AML patients [11]. This agent was designed theoretically to enhance directed anti-leukemic efficacy with less non-specific toxicity against normal tissues. Gemtuzumab is a recombinant humanized IgG4 kappa antibody with high affinity to the CD33 receptor without intrinsic anti-leukemic activity. This antibody is attached via a specific linker to the cytotoxic derivative of calicheamicin. Once bound to CD33, the ADC is internalized. Following internalization, GO is trafficked from endosomes to lysosomes where linker cleavage occurs in the acidic environment of the lysosome. The free calicheamicin derivative now trafficks to the nucleus, where it binds to DNA and induces double strand breaks, leading to arrest of cell cycle and apoptosis [12]. Theoretically, pluripotent stem cells and non-hematopoietic cells are not affected by GO as they lack CD33 expression.
A review of FDA-approved acute myeloid leukemia therapies beyond ‘7 + 3’
Published in Expert Review of Hematology, 2021
Alexandre Bazinet, Sarit Assouline
Gemtuzumab ozogamicin (GO) was the first example of an antibody-drug conjugate (ADC) used in cancer treatment. It uses a humanized anti-CD33 antibody to deliver the cytotoxic compound calicheamicin. Malignant myeloblasts express CD33 in over 90% of AML cases [6]. CD33 is also found on leukemia stem cells (LSCs) in some AML subtypes [7]. Upon binding CD33, GO is internalized and calicheamicin is released in the lysosome, causing DNA double-strand breaks and cell death [8]. Calicheamicin is over 1000 times more potent than doxorubicin and is highly damaging to normal cells [9]. It therefore requires targeted delivery to minimize toxicity.