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

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.

Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?

“…In a recent phase I/II study evaluating YS110 in patients with advanced MPM, it was generally well tolerated and showed some efficacy as a salvage therapy in difficult-to-treat patients (Table 1) [67,68]. The YS110-based antibodydrug conjugate Y-TR1 containing triptolide (TR-1, Nrf2 inhibitor) is in the preclinical phase [69,70]. The clinical utility of these mAbs deserves future attention.…”

Serum soluble CD26/DPP4 titer variation is a potential prognostic biomarker in cancer therapy with a humanized anti-CD26 antibody

“…Another important mechanism of action of YS110 was the nuclear translocation of CD26 molecules by internalization of the CD26-YS110 complexes from the cell surface to inhibit proliferation of MM cells via suppression of POLR2A gene expression, a component of RNA polymerase II. However, in the case of CD26-expressing non-neoplastic cells such as human embryonic kidney HEK293 cells or normal T lymphocytes, the CD26-YS110 complex was not translocated into the nucleus [22,23]. Moreover, internalization of the CD26-antibody complexes was dependent on the epitope of CD26 recognized by speci c mAb.…”

Phase 2 Study of YS110, a Recombinant Humanized Anti-CD26 Monoclonal Antibody, in Japanese Patients With Advanced Malignant Pleural Mesothelioma

“…To date, in vitro data indicate that a humanized monoclonal antibody against CD26 induces the inhibition of cell growth in MPM cells by cell-cycle regulation and repression of transcriptional genes. 8,[13][14][15] The inhibitory effect on CD26-positive cell proliferation in vitro was more marked in cells exhibiting stronger versus weaker CD26 positivity. 16 In addition, the antitumor effects of YS110 were exhibited in a CD26-positive, tumor-bearing mouse model, 13 suggesting an association between CD26 expression and anti-CD26 antibody activity in vivo and in vitro.…”