Abstract
Two systems of antibody-drug conjugates (ADCs), noncleavable H32-DM1 and cleavable H32-VCMMAE, were developed by using different linkers and drugs attached to the anti-HER2 antibody H32, which is capable of cell internalization. Activated functional groups, including an N-hydroxysuccinimidyl (NHS) ester and a maleimide, were utilized to make the ADCs. Mass spectrometry, hydrophobic interaction chromatography, polyacrylamide gel electrophoresis, and in vitro cell assays were performed to analyze and optimize the ADCs. Several H32-VCMMAE ADCs were established with higher DARs and greater synthetic yields without compromising potency. The anticancer efficacy of H32-DM1 was 2- to 8-fold greater than that of Kadcyla®. The efficacy of H32-VCMMAE was in turn better than that of H32-DM1. The anticancer efficacy of these ADCs against N87, SK-BR-3 and BT474 cells was in the following order: H32-VCMMAE series > H32-DM1 series > Kadcyla®. The optimal DAR for H32-VCMMAE was found to be 6.6, with desirable attributes including good cell penetration, a releasable payload in cancer cells, and high potency. Our results demonstrated the potential of H32-VCMMAE as a good ADC candidate.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Ado-Trastuzumab Emtansine / chemistry
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Ado-Trastuzumab Emtansine / pharmacology
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Antibodies, Monoclonal, Humanized / chemistry
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Antibodies, Monoclonal, Humanized / pharmacology*
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Antineoplastic Agents, Immunological / chemistry
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Antineoplastic Agents, Immunological / pharmacology
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Cell Survival / drug effects
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Female
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Humans
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Immunoconjugates / chemistry
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Immunoconjugates / pharmacology*
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Inhibitory Concentration 50
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Oligopeptides / chemistry
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Oligopeptides / pharmacology
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Receptor, ErbB-2 / immunology*
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Receptor, ErbB-2 / metabolism*
Substances
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents, Immunological
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Immunoconjugates
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Oligopeptides
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ERBB2 protein, human
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Receptor, ErbB-2
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Ado-Trastuzumab Emtansine
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monomethyl auristatin E
Grants and funding
This work was supported by the Ministry of Science and Technology (MOST107-0210-01-19-01) and the Program for Translational Innovation of Biopharmaceutical Development–Technology Supporting Platform Axis (AS-KPQ-106-TSPA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.