Antitumor effect of novel anti-podoplanin antibody NZ-12 against malignant pleural mesothelioma in an orthotopic xenograft model

Our plain-English summary of Antitumor effect of novel anti-podoplanin antibody NZ-12 against malignant pleural mesothelioma in an orthotopic xenograft model, by S. Abe, M.K. Kaneko, Y. Tsuchihashi, et al (Cancer Science, 2016).

The study

• Authors: S. Abe, M.K. Kaneko, Y. Tsuchihashi, T. Izumi, S. Ogasawara, N. Okada, C. Sato, M. Tobiume, K. Otsuka, L. Miyamoto, K. Tsuchiya, K. Kawazoe, Y. Kato, Y. Nishioka
• Journal: Cancer Science
• Published: 2016;107(9):1198-205
• Cited by: 49 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Podoplanin (aggrus) is highly expressed in several types of cancers, including malignant pleural mesothelioma (MPM). Previously, we developed a rat anti-human podoplanin mAb, NZ-1, and a rat-human chimeric anti-human podoplanin antibody, NZ-8, derived from NZ-1, which induced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity against podoplanin-positive MPM cell lines. In this study, we showed the antitumor effect of NZ-1, NZ-8, and NZ-12, a novel rat-human chimeric anti-human podoplanin antibody derived from NZ-1, in an MPM orthotopic xenograft SCID mouse model. Treatment with NZ-1 and rat NK (CD161a(+) ) cells inhibited the growth of tumors and the production of pleural effusion in NCI-H290/PDPN or NCI-H226 orthotopic xenograft mouse models. NZ-8 and human natural killer (NK) (CD56(+) ) cells also inhibited tumor growth and pleural effusion in MPM orthotopic xenograft mice. Furthermore, NZ-12 induced potent ADCC mediated by human MNC, compared with either NZ-1 or NZ-8. Antitumor effects were observed following treatment with NZ-12 and human NK (CD56(+) ) cells in MPM orthotopic xenograft mice. In addition, combined immunotherapy using the ADCC activity of NZ-12 mediated by human NK (CD56(+) ) cells with pemetrexed, led to enhanced antitumor effects in MPM orthotopic xenograft mice. These results strongly suggest that combination therapy with podoplanin-targeting immunotherapy using both NZ-12 and pemetrexed might provide an efficacious therapeutic strategy for the treatment of MPM.

© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

In plain English

This was a laboratory and animal study of experimental antibody treatments for malignant pleural mesothelioma (MPM). It did not examine asbestos exposure. The antibodies target podoplanin, a protein found on mesothelioma cells. The authors tested three related antibodies, NZ-1, NZ-8 and a new one, NZ-12. They used human MPM cell lines grown in the lab, and SCID mice (groups of 5) whose chest cavities were injected with human MPM cells. Each antibody given together with natural killer (NK) immune cells reduced chest tumor growth and fluid build-up around the lungs (pleural effusion). NZ-1 or NZ-12 given without NK cells did not. In lab tests, NZ-12 caused significantly more immune-cell killing of cancer cells than NZ-1 or NZ-8. Adding the chemotherapy drug pemetrexed to NZ-12 plus human NK cells reduced tumors and effusion significantly more than the antibody treatment or pemetrexed alone. The article reports its results in figures rather than as numbers in the text. The authors concluded that this combination produced enhanced antitumor effects in their mouse model.

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 experiments on human mesothelioma cell lines and animal experiments in a mouse model in which human MPM cells were placed in the chest cavity (orthotopic xenograft model)
• Who was studied: Four human MPM cell lines (NCI-H290, NCI-H226, ACC-MESO-1, ACC-MESO-4), including NCI-H290 cells altered to carry podoplanin (NCI-H290/PDPN). Also male SCID mice, 5 per group, injected in the chest cavity with NCI-H290/PDPN or NCI-H226 cells. Japan (Tokushima University).
• Exposure: No asbestos exposure was studied. The treatments tested were anti-podoplanin antibodies NZ-1 (rat), NZ-8 and NZ-12 (rat-human chimeric), given with rat or human NK cells, and the chemotherapy drug pemetrexed (100 mg/kg) in combination with NZ-12.
• Main results:
  • In NCI-H290/PDPN mice, NZ-1 injected into the chest with rat NK cells almost entirely inhibited tumor growth and pleural effusion at 3 weeks.
  • NZ-1 alone did not produce an antitumor effect in this model.
  • In both NCI-H290/PDPN and NCI-H226 mice, NZ-1 given by abdominal injection with rat NK cells significantly inhibited chest tumor growth and pleural effusion compared with either treatment alone.
  • In NCI-H290/PDPN mice, NZ-8 with human NK cells significantly inhibited tumor weight and pleural effusion compared with NZ-8 or human NK cells alone.
  • In lab tests with human immune cells, NZ-12 caused significantly more antibody-dependent cell killing (ADCC) of podoplanin-positive MPM cells than NZ-1 or NZ-8.
  • NZ-12 also caused complement-dependent killing (CDC) of podoplanin-positive MPM cells in the lab.
  • In NCI-H290/PDPN mice, NZ-12 with human NK cells significantly inhibited tumor weight and pleural effusion.
  • NZ-12 alone did not inhibit tumor growth.
  • In the lab, pemetrexed did not change podoplanin levels on NCI-H290/PDPN cells.
  • In the lab, pemetrexed did not reduce the immune-cell killing caused by NZ-12.
  • In mice, NZ-12 plus human NK cells plus pemetrexed significantly reduced chest tumor growth and pleural effusion compared with the NZ-12 immunotherapy or pemetrexed alone.
• The authors' conclusion: The authors concluded that NZ-12, which induced potent immune-cell killing mediated by human NK cells, combined with pemetrexed produced enhanced antitumor effects in their MPM mouse model. They suggested this combination could be a promising treatment strategy for MPM.
• Limitations the authors state:
  • The authors state that the reason NZ-12 caused more immune-cell killing than NZ-8 is unknown.
  • The authors state that the detailed mechanism of the combined effect of NZ-12 immunotherapy and pemetrexed is unclear.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Podoplanin (D2-40), Pleural Mesothelioma, Pleural Effusion, Immunotherapy, Pemetrexed (Alimta).

Related studies

• Antitumor activity of chLpMab-2, a human-mouse chimeric cancer-specific antihuman podoplanin antibody, via antibody-dependent cellular cytotoxicity — M.K. Kaneko, S. Yamada, et al. (2017)
• Therapeutic efficacy evaluation of radioimmunotherapy with 90 Y-labeled anti-podoplanin antibody NZ-12 for mesothelioma — H. Sudo, A.B. Tsuji, et al. (2019)
• Establishment of Mouse Monoclonal Antibody LpMab-13 Against Human Podoplanin — S. Ogasawara, M.K. Kaneko, et al. (2016)
• Therapeutic antitumor efficacy of anti-epidermal growth factor receptor antibody, cetuximab, against malignant pleural mesothelioma — J. Kurai, H. Chikumi, et al. (2012)
• Antitumor activity of anti-C-ERC/mesothelin monoclonal antibody in vivo — K. Inami, M. Abe, et al. (2010)
• Epitope Mapping of Monoclonal Antibody PMab-233 Against Tasmanian Devil Podoplanin — M. Sano, M.K. Kaneko, et al. (2019)

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