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Structure of N-acetyl, gamma calicheamicin conjugate: Mylotarg.
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toxins-03-00848-f017: Structure of N-acetyl, gamma calicheamicin conjugate: Mylotarg.

Mentions: A series of conjugates of calicheamicins with the CTM01 anti-MUC1 antibody has been reported [140] but the first and thus far the sole mAb linked to a cytotoxic payload that has been given regulatory approval is Wyeth’s gemtuzumab ozogamicin (Mylotarg; Figure 17) [141,142]. The drug was approved by the US Food and Drug Administration in year 2000 for use in patients over sixty suffering from relapsed acute myelocytic leukemia, the commonest form of leukemia in adults. Gemtuzumab ozogamicin consists of N-acetyl-γ-calicheamicin covalently attached to the humanized anti-CD33 IgG4 κ antibody (hP67.6) via a bifunctional linker. The 4-(4-acetylphenoxy)butanoic acid moiety provides attachment to surface-exposed lysines of the antibody through an amide bond, and forms an acyl hydrazone linkage with N-acetyl-γ-calicheamicin dimethyl hydrazide. Typically, a drug loading of 2 to 3 molecules of calicheamicin per molecule of mAb can be achieved. Upon internalization of the ADC, the calicheamicin prodrug is released by hydrolysis of the hydrazone in the lysosomes of the CD33+ target cells, at least in vitro. Indeed the hydrolysis of hydrazone linkage at 37 °C over 24 h increased from 6% at pH 7.4 to 97% at pH 4.5 [143]. The enediyne drug is then activated by reductive cleavage of the disulfide bond; and in order to prevent premature release of calicheamicin by circulating reduced thiols, such as glutathione, the disulfide linkage is stabilized by two methyl groups close to the disulfide.

Immunotoxins and Anticancer Drug Conjugate Assemblies: The Role of the Linkage between Components

Dosio F, Brusa P, Cattel L - Toxins (Basel) (2011)

Bottom Line: Immunotoxins and antibody-drug conjugates are protein-based drugs combining a target-specific binding domain with a cytotoxic domain.During the preparation of immunoconjugates by chemical synthesis, the choice of the hinge component joining the two building blocks is of paramount importance: the conjugate must remain stable in vivo but must afford efficient release of the toxic moiety when the target is reached.Vast efforts have been made, and the present article reviews strategies employed in developing immunoconjugates, focusing on the evolution of chemical linkers.

Affiliation: Department of Drug Science and Technology, University of Torino, Torino 10125, Italy. franco.dosio@unito.it

ABSTRACT
Immunotoxins and antibody-drug conjugates are protein-based drugs combining a target-specific binding domain with a cytotoxic domain. Such compounds are potentially therapeutic against diseases including cancer, and several clinical trials have shown encouraging results. Although the targeted elimination of malignant cells is an elegant concept, there are numerous practical challenges that limit conjugates' therapeutic use, including inefficient cellular uptake, low cytotoxicity, and off-target effects. During the preparation of immunoconjugates by chemical synthesis, the choice of the hinge component joining the two building blocks is of paramount importance: the conjugate must remain stable in vivo but must afford efficient release of the toxic moiety when the target is reached. Vast efforts have been made, and the present article reviews strategies employed in developing immunoconjugates, focusing on the evolution of chemical linkers.

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