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 Hayashi,Nishida Nishida,Morimoto Morimoto,Madokoro Madokoro,Yanagawa Yanagawa,Sakamoto Sakamoto,Yamada Yamada

doi:10.3390/cancers11081138

Hayashi Hayashi, Nishida Nishida + Show 5 more

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https://doi.org/10.3390/cancers11081138

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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.

Highlights

CD26 is a type II glycoprotein that has intrinsic dipeptidyl peptidase IV (DPPIV) activity [1] and is implicated in broad and various physiological processes, including metabolism of glucose, activation ofT lymphocytes, and cell adhesion [2,3]
TR-1 was reduced by the immobilized tris(2-carboxyethyl) phosphine (TCEP) reducing gel (Thermo Scientific Inc., Waltham, MA, USA) from the S-S dimer before the assay
It was previously reported that the functional blockade of one of the subunits of RNA polymerase II, POLR2A, by RNAi strategies and treatment with chemical compounds such as α-amanitin resulted in growth inhibition of cancer cells [20,21,22]

Summary

Introduction

CD26 is a type II glycoprotein that has intrinsic dipeptidyl peptidase IV (DPPIV) activity [1] and is implicated in broad and various physiological processes, including metabolism of glucose, activation ofT lymphocytes, and cell adhesion [2,3]. We have already generated anti-CD26 monoclonal antibodies (mAbs) that have certain inhibitory effects against the growth of tumor cells and xenografted tumors [9,10]. MAb YS110, that binds to the cell membrane-proximal glycosylated region starting at the 20-amino acid flexible stalk region of human CD26, has showed anti-tumor effects in malignant mesothelioma (MM) models [4]. The first-in-human phase 1/2 study of anti-CD26 mAbs in advanced cases with CD26-expressing mesothelioma and renal cell carcinoma has been done in France. Anti-CD26 mAbs are well tolerated up to 6 mg/kg Q1W, which has been defined as RP2D, with encouraging prolonged disease stabilizations observed in a number of patients with advanced/refractory mesothelioma [11]

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