A humanized anti-CD26 monoclonal antibody inhibits cell growth of malignant mesothelioma via retarded G2/M cell cycle transition

Our plain-English summary of A humanized anti-CD26 monoclonal antibody inhibits cell growth of malignant mesothelioma via retarded G2/M cell cycle transition, by M. Hayashi, H. Madokoro, K. Yamada, et al (Cancer Cell International, 2016).

The study

• Authors: M. Hayashi, H. Madokoro, K. Yamada, H. Nishida, C. Morimoto, M. Sakamoto, T. Yamada
• Journal: Cancer Cell International
• Published: 2016;16:35
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant Mesothelioma (MM) is a highly aggressive tumor with poor prognosis. Multimodal treatments and novel molecular targeted therapies against MM are in high demand in order treat this disease effectively. We have developed a humanized monoclonal antibody YS110 against CD26 expressed in 85 % of MM cases. CD26 is thought to be involved in tumor growth and invasion by interacting with collagen and fibronectin, or affecting signal transduction processes.

Methods: We evaluated the direct anti-tumor effect of YS110 against MM cell lines, NCI-H2452 and JMN, and investigated its effects on cell cycle and on the cell cycle regulator molecules. In addition, we investigated synergistic effects of YS110 and anti-tumor agent pemetrexed (PMX) against MM cell line both in vitro and in vivo.

Results: YS110 suppressed the proliferation of NCI-H2452 cells by approximately 20 % in 48 h. Based on cell cycle analysis, percentage of cells in G2/M phase increased 8.0 % on the average after YS110 treatment; in addition, cell cycle regulator p21 cip/waf1 was increased and cyclin B1 was decreased after YS110 treatment. Inhibitory phosphorylation of both cdc2 (Tyr15) and cdc25C (Ser216) were elevated. Furthermore, activating phosphorylation of p38 MAPK (Thr180/Tyr182) and ERK1/2 (Thr202/Tyr204) were augmented at 24 h after YS110 treatment. PMX rapidly induced CD26 expression on cell surface and the treatment with both YS110 and PMX inhibited in vivo tumor growth accompanied by a synergistic reduction in the MIB-1 index.

Conclusion: This is a first report of a novel anti-proliferative mechanism of the humanized anti-CD26 monoclonal antibody YS110, which resulted in G2/M cell cycle delay through regulation of quantity and activity of various cell cycle regulating molecules.

In plain English

This laboratory study tested an experimental antibody, YS110, which targets CD26, a protein found on many mesothelioma cells. It did not study patients or asbestos exposure. The authors treated mesothelioma cell lines in dishes and, together with the chemotherapy drug pemetrexed, mesothelioma tumors grown from JMN cells in mice. In NCI-H2452 cells, YS110 reduced growth by at most 18.3 %. Averaged over ten experiments, it significantly increased the share of cells held at the G2/M stage of cell division. In another cell line, NCI-H28, a 5 % average increase was not statistically significant. The authors linked the delay to changes in cell-cycle proteins and to the ERK1/2 signaling pathway. Pemetrexed rapidly raised CD26 levels in the cells. In mice, YS110 alone did not significantly reduce tumor weight, while pemetrexed did. The combination reduced tumor weight and a growth marker (MIB-1 index) more than either drug alone. The authors noted that YS110's direct effect was limited to about 20 % and that how ERK1/2 activation causes the delay is still unknown.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study using human mesothelioma cell lines grown in culture plus an animal (mouse xenograft) experiment
• Who was studied: Three CD26-positive human malignant mesothelioma cell lines (NCI-H2452, NCI-H28, JMN). JMN tumors were also grown in immunodeficient NOG mice; the methods give 3 mice per treatment group.
• Exposure: No asbestos exposure was studied. The treatments were the humanized anti-CD26 monoclonal antibody YS110 (mainly 2 μg/mL in cell experiments) and the chemotherapy drug pemetrexed (PMX), alone and combined.
• Main results:
  • In NCI-H2452 cells, maximum growth inhibition by YS110 was 18.3 % at 250 μg/mL. The figure legend gives 18.6 %.
  • In NCI-H2452 cells, averaged over ten experiments, the percentage of cells in G2/M phase was significantly increased after YS110 treatment (p less than 0.05).
  • In NCI-H28 cells, the G2/M percentage rose by 5 % on average after YS110, but this was not statistically significant.
  • At 24 h after YS110 treatment, p21 increased and cyclin B1 decreased in NCI-H2452 cells.
  • The MEK1/2 inhibitor U0126 blocked the G2/M arrest caused by YS110; the p38 inhibitor SB203580 did not.
  • Pemetrexed (10 μM) rapidly induced CD26 protein expression in JMN and NCI-H2452 cells, starting at 1 h.
  • In mice with JMN tumors, YS110 alone did not significantly reduce tumor weight, while pemetrexed alone did (p less than 0.05).
  • In mice, YS110 plus pemetrexed reduced tumor weight compared with either single treatment (p less than 0.05).
  • The MIB-1 index (a marker of dividing cells) was significantly lower after YS110 or pemetrexed alone than in controls.
  • The combined treatment lowered the MIB-1 index further than either single treatment.
• The authors' conclusion: The authors concluded that YS110 suppressed proliferation of CD26-positive mesothelioma cell lines through a novel mechanism causing G2/M cell cycle delay through ERK1/2 phosphorylation, and that pemetrexed was identified as a CD26 inducer.
• Limitations the authors state:
  • The direct anti-proliferative effect of YS110 in cell culture was limited to about 20 %.
  • The mechanism by which ERK1/2 activation produces the G2/M delay remains unknown.
  • The combined treatment did not significantly change cell-cycle proportions compared with either single treatment.

Topics

Medical terms in this study, explained in our Lexicon: Monoclonal Antibody, Mesothelioma, Prognosis, Collagen, Synergistic Effect, Pemetrexed (Alimta).

Related studies

• Nuclear localization of CD26 induced by a humanized monoclonal antibody inhibits tumor cell growth by modulating of POLR2A transcription — K. Yamada, M. Hayashi, et al. (2013)
• Phase 2 Study of YS110, a Recombinant Humanized Anti-CD26 Monoclonal Antibody, in Japanese Patients With Advanced Malignant Pleural Mesothelioma — K. Nakagawa, T. Kijima, et al. (2021)
• Localization of CD26/DPPIV in nucleus and its nuclear translocation enhanced by anti-CD26 monoclonal antibody with anti-tumor effect — K. Yamada, M. Hayashi, et al. (2009)
• Connective tissue growth factor-specific monoclonal antibody inhibits growth of malignant mesothelioma in an orthotopic mouse model — Y. Ohara, S.H. Chew, et al. (2018)
• Phase I study of YS110, a recombinant humanized monoclonal antibody to CD26, in Japanese patients with advanced malignant pleural mesothelioma — M. Takeda, Y. Ohe, et al. (2019)
• Phase 1b Multicenter Study of SG001, a Humanized Anti-PD-1 Antibody, in Patients with Advanced Solid Tumors — J. Fang, O. Jiang, et al. (2025)

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