Cancer Science 2016 June 13 [Epub ahead of print] [Link]
Abe S, Kaneko MK, Tsuchihashi Y, Izumi T, Ogasawara S, Okada N, Sato C, Tobiume M, Otsuka K, Miyamoto L, Tsuchiya K, Kawazoe K, Kato Y, Nishioka Y.
Podoplanin (Aggrus) is highly expressed in several types of cancers, including malignant pleural mesothelioma (MPM). Previously, we developed a rat anti-human podoplanin monoclonal antibody, 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 (CDC) against podoplanin-positive MPM cell lines. In this study, we demonstrated 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 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 a combination therapy of both podoplanin-targeting immunotherapy using NZ-12 and pemetrexed might provide an efficacious therapeutic strategy for the treatment of MPM.