Novel antibody-drug conjugate with Anti-CD26 humanized monoclonal antibody and transcription factor IIH (TFIIH) inhibitor, triptolide, inhibits tumor growth via impairing mRNA synthesis

Mutsumi Hayashi, Hiroko Madokoro, Koji Yamada, Hiroko Nishida, Chikao Morimoto, Michiie Sakamoto, Hiroshi Yanagawa, Taketo Yamada

Research output: Contribution to journalArticle

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-(Nmaleimidomethyl)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 dosedependent 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 YTR1 is a unique antitumor ADC and functions against Pol II.

Original languageEnglish
Article number1138
JournalCancers
Volume11
Issue number8
DOIs
Publication statusPublished - 2019 Aug 1

Fingerprint

Transcription Factor TFIIH
Antibodies, Monoclonal, Humanized
Cell Line
Messenger RNA
Antibodies
Growth
General Transcription Factors
Pharmaceutical Preparations
Neoplasms
RNA Polymerase II
Antineoplastic Agents
Cell Survival
Leukemia
Monoclonal Antibodies
triptolide
In Vitro Techniques

Keywords

  • Antibody drug conjugate
  • CD26
  • Malignant mesothelioma
  • RNA polymerase II
  • Targeted therapy
  • Triptolide

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Novel antibody-drug conjugate with Anti-CD26 humanized monoclonal antibody and transcription factor IIH (TFIIH) inhibitor, triptolide, inhibits tumor growth via impairing mRNA synthesis. / Hayashi, Mutsumi; Madokoro, Hiroko; Yamada, Koji; Nishida, Hiroko; Morimoto, Chikao; Sakamoto, Michiie; Yanagawa, Hiroshi; Yamada, Taketo.

In: Cancers, Vol. 11, No. 8, 1138, 01.08.2019.

Research output: Contribution to journalArticle

Hayashi, Mutsumi ; Madokoro, Hiroko ; Yamada, Koji ; Nishida, Hiroko ; Morimoto, Chikao ; Sakamoto, Michiie ; Yanagawa, Hiroshi ; Yamada, Taketo. / Novel antibody-drug conjugate with Anti-CD26 humanized monoclonal antibody and transcription factor IIH (TFIIH) inhibitor, triptolide, inhibits tumor growth via impairing mRNA synthesis. In: Cancers. 2019 ; Vol. 11, No. 8.
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AU - Yamada, Koji

AU - Nishida, Hiroko

AU - Morimoto, Chikao

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AU - Yanagawa, Hiroshi

AU - Yamada, Taketo

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AB - 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-(Nmaleimidomethyl)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 dosedependent 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 YTR1 is a unique antitumor ADC and functions against Pol II.

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