Calicheamicin Antibody-Drug Conjugates with Improved Properties

Calicheamicin antibody-drug conjugates (ADCs) are effective therapeutics for leukemias with two recently approved in the United States: Mylotarg (gemtuzumab ozogamicin) targeting CD33 for acute myeloid leukemia and Besponsa (inotuzumab ozogamicin) targeting CD22 for acute lymphocytic leukemia. Both...

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Bibliographic Details
Published in:Molecular cancer therapeutics 2021-06, Vol.20 (6), p.1112-1120
Main Authors: Vollmar, Breanna S, Frantz, Chris, Schutten, Melissa M, Zhong, Fiona, Del Rosario, Geoffrey, Go, Mary Ann T, Yu, Shang-Fan, Leipold, Douglas D, Kamath, Amrita V, Ng, Carl, Xu, Keyang, Dela Cruz-Chuh, Josefa, Kozak, Katherine R, Chen, Jinhua, Xu, Zijin, Wai, John, Adhikari, Pragya, Erickson, Hans K, Dragovich, Peter S, Polson, Andrew G, Pillow, Thomas H
Format: Article
Language:English
Subjects:
Animals
Antibiotics, Antineoplastic - pharmacology
Antibiotics, Antineoplastic - therapeutic use
Calicheamicins - pharmacology
Calicheamicins - therapeutic use
Disease Models, Animal
Humans
Immunoconjugates - pharmacology
Immunoconjugates - therapeutic use
Mice
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Summary:Calicheamicin antibody-drug conjugates (ADCs) are effective therapeutics for leukemias with two recently approved in the United States: Mylotarg (gemtuzumab ozogamicin) targeting CD33 for acute myeloid leukemia and Besponsa (inotuzumab ozogamicin) targeting CD22 for acute lymphocytic leukemia. Both of these calicheamicin ADCs are heterogeneous, aggregation-prone, and have a shortened half-life due to the instability of the acid-sensitive hydrazone linker in circulation. We hypothesized that we could improve upon the heterogeneity, aggregation, and circulation stability of calicheamicin ADCs by directly attaching the thiol of a reduced calicheamicin to an engineered cysteine on the antibody via a disulfide bond to generate a linkerless and traceless conjugate. We report herein that the resulting homogeneous conjugates possess minimal aggregation and display high stability with 50% of the drug remaining conjugated to the antibody after 21 days. Furthermore, these calicheamicin ADCs are highly efficacious in mouse models of both solid tumor (HER2 breast cancer) and hematologic malignancies (CD22 non-Hodgkin lymphoma). Safety studies in rats with this novel calicheamicin ADC revealed an increased tolerability compared with that reported for Mylotarg. Overall, we demonstrate that applying novel linker chemistry with site-specific conjugation affords an improved, next-generation calicheamicin ADC.
ISSN:1535-7163
1538-8514
DOI:10.1158/1535-7163.MCT-20-0035