Anti-CD137 monoclonal antibody enhances trastuzumab-induced, natural killer cell-mediated cytotoxicity against pancreatic cancer cell lines with low human epidermal growth factor-like receptor 2 expression

Masu, T.; Atsukawa, M.; Nakatsuka, K.; Shimizu, M.; Miura, D.; Arai, T.; Harimoto, H.; Kondo, C.; Kaneko, K.; Futagami, S.; Kawamoto, C.; Takahashi, H.; Iwakiri, K.

doi:10.1101/361279

bioRxiv · 10.1101/361279

Anti-CD137 monoclonal antibody enhances trastuzumab-induced, natural killer cell-mediated cytotoxicity against pancreatic cancer cell lines with low human epidermal growth factor-like receptor 2 expression

Masu, T.·Atsukawa, M.·Nakatsuka, K.·Shimizu, M.·Miura, D.·Arai, T.·Harimoto, H.·Kondo, C.·Kaneko, K.·Futagami, S.·Kawamoto, C.·Takahashi, H.·Iwakiri, K.

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Abstract

BackgroundBecause human epidermal growth factor-like receptor (HER) 2 is expressed on the surface of human pancreatic carcinoma cells to varying degrees, trastuzumab, an anti-HER2 monoclonal antibody (mAb), is expected to exert antibody-dependent, natural killer (NK) cell-mediated cytotoxicity (ADCC) against the cells. However, some reports found that the effect of trastuzumab against human pancreatic carcinoma cells was limited because most express only limited HER2.\n\nMethodsWe examined whether anti-CD137 stimulating mAb could enhance trastuzumab-mediated ADCC against Panc-1, a human pancreatic cancer cell line with low HER2 expression, in vitro.\n\nResultsSupplementation of anti-CD137 mAb could improve trastuzumab-mediated ADCC against Panc-1 which was insufficient without this stimulating antibody. The ADCC differed in individual cells, and this was related to the expression of CD137 on the surface of NK cells after trastuzumab stimulation in association with the Fc{gamma}-RIIIA polymorphism. NK cells with Fc{gamma}-RIIIA-VV/VF showed high levels of ADCC against Panc-1, but those with Fc{gamma}-RIIIA-FF did not show optimal ADCC. In addition, trastuzumab-mediated ADCC against the human pancreatic cancer cell line Capan-1 with high HER2 expression was generally high and not affected by the Fc{gamma}-RIIIA polymorphism.\n\nConclusionsThese results demonstrated that in Fc{gamma}-RIIIA-VV/VF-carrying hosts, trastuzumab plus CD137 mAb could induce effective ADCC against HER2-low-expressing pancreatic cancer cells. This also indicates the therapeutic potential for unresectable human pancreatic cancer, in which HER-2 expression is generally low.

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Masu, T., Atsukawa, M., Nakatsuka, K., Shimizu, M., Miura, D., Arai, T., Harimoto, H., Kondo, C., Kaneko, K., Futagami, S., Kawamoto, C., Takahashi, H., Iwakiri, K.. 2018-07-03. Anti-CD137 monoclonal antibody enhances trastuzumab-induced, natural killer cell-mediated cytotoxicity against pancreatic cancer cell lines with low human epidermal growth factor-like receptor 2 expression. https://doi.org/10.1101/361279

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