Abstract
In the search for novel payloads to design new antibody-drug conjugates (ADC), marine compounds represent an interesting opportunity given their unique chemical features. PM050489 is a marine compound that binds β-tubulin at a new site and disrupts the microtubule network, hence leading to mitotic aberrations and cell death. PM050489 has been conjugated to trastuzumab via Cys residues through a noncleavable linker, and the resulting ADC, named MI130004, has been studied. Analysis of MI130004 delivered data consistent with the presence of two molecules of PM050489 per antibody molecule, likely bound to both sides of the intermolecular disulfide bond connecting the antibody light and heavy chains. The antitumor activity of MI130004 was analyzed in vitro and in vivo in different cell lines of diverse tumor origin (breast, ovary, and gastric cancer) expressing different levels of HER2. MI130004 showed very high in vitro potency and good selectivity for tumor cells that overexpressed HER2. At the cellular level, MI130004 impaired tubulin polymerization, causing disorganization and disintegration of the microtubule network, which ultimately led to mitotic failure, mirroring the effect of its payload. Treatment with MI130004 in mice carrying histologically diverse tumors expressing HER2 induced a long-lasting antitumor effect with statistically significant inhibition of tumor growth coupled with increases in median survival time compared with vehicle or trastuzumab. These results strongly suggest that MI130004 is endowed with remarkable anticancer activity and confirm the extraordinary potential of marine compounds for the design of new ADCs. Mol Cancer Ther; 17(4); 786-94. ©2018 AACR.
Highlights
Antibody–drug conjugates (ADC) are a relatively novel class of therapeutic agents that have drawn the attention of the pharmaceutical industry in the past decade
Mylotarg was withdrawn from market in 2010, two new ADCs were launched soon thereafter: Adcetris in 2011, for the treatment of Hodgkin lymphoma as well as systemic anaplastic large cell lymphoma [2], and Kadcyla in 2013 for treating HER2-positive metastatic breast cancer [3]
Despite the evident need for novel payloads that might help to overcome future resistance, a close study to the current pipeline shows that the vast majority of the novel ADCs under clinical investigation includes cytotoxic warheads belonging to the same chemical families than those of Mylotarg, Adcetris and Kadcyla, that is, calicheamicins, auristatins, and maytansinoids, respectively
Summary
Antibody–drug conjugates (ADC) are a relatively novel class of therapeutic agents that have drawn the attention of the pharmaceutical industry in the past decade. Mylotarg was withdrawn from market in 2010, two new ADCs were launched soon thereafter: Adcetris (brentuximab vedotin) in 2011, for the treatment of Hodgkin lymphoma as well as systemic anaplastic large cell lymphoma [2], and Kadcyla (trastuzumab emtansine) in 2013 for treating HER2-positive metastatic breast cancer [3]. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
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