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Open AccessArticle

Novel Antibody-Drug Conjugate with Anti-CD26 Humanized Monoclonal Antibody and Transcription Factor IIH (TFIIH) Inhibitor, Triptolide, Inhibits Tumor Growth via Impairing mRNA Synthesis

1
Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
2
Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
3
Department of Biochemistry, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan
4
Department of Therapy Development and Innovation for Immune Disorders and Cancers, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
5
Department of Fundamental Science and Technology, Keio University School of Science and Technology, 3-14-1 Hiyoshi, Kouhoku-ku, Yokohama City 233-8522, Kanagawa, Japan
6
IDAC Theranostics Inc., 1-1-48 Suehirocho, Tsurumi-ku, Yokohama City 230-0045, Kanagawa, Japan
7
Department of Pathology, Saitama Medical University, 38 Morohongo, Moroyama-machi, Saitama 350-0495, Japan
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(8), 1138; https://doi.org/10.3390/cancers11081138
Received: 17 July 2019 / Accepted: 5 August 2019 / Published: 8 August 2019
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Abstract

Here, we report a novel antibody drug conjugate (ADC) with the humanized anti-CD26 monoclonal antibody YS110 and triptolide (TR-1). YS110 has an inhibitory activity against the CD26-positive tumor growth via the immunological and direct pathway, such as intra-nuclear transportation of CD26 and YS110, and suppressed transcription of RNA polymerase II (Pol II) subunit POLR2A. The ADC conjugated with YS110 and an antitumor compound triptolide (TR-1), which is an inhibitor for TFIIH, one of the general transcription factors for Pol II was developed. YS110 and triptolide were crosslinked by the heterobifunctional linker succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) and designated Y-TR1. Antitumor efficacy of Y-TR1 against malignant mesothelioma and leukemia cell lines were assessed by the in vitro cell viability assay and in vivo assay using xenografted mouse models. Y-TR1 showed significant cytotoxicity against CD26-positive cell lines but not CD26-negative counterparts in a dose-dependent manner via suppression of mRNA synthesis by impairment of the Pol II activity. The tumors in xenografted mice administered Y-TR1 was smaller than that of the unconjugated YS110 treated mice without severe toxicity. In conclusion, the novel compound Y-TR1 showed antitumor properties against CD26-positive cancer cell lines both in vitro and in vivo without toxicity. The Y-TR1 is a unique antitumor ADC and functions against Pol II. View Full-Text
Keywords: antibody drug conjugate; targeted therapy; CD26; triptolide; RNA polymerase II; malignant mesothelioma antibody drug conjugate; targeted therapy; CD26; triptolide; RNA polymerase II; malignant mesothelioma
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Hayashi, M.; Madokoro, H.; Yamada, K.; Nishida, H.; Morimoto, C.; Sakamoto, M.; Yanagawa, H.; Yamada, T. Novel Antibody-Drug Conjugate with Anti-CD26 Humanized Monoclonal Antibody and Transcription Factor IIH (TFIIH) Inhibitor, Triptolide, Inhibits Tumor Growth via Impairing mRNA Synthesis. Cancers 2019, 11, 1138.

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