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

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.

Therapeutic efficacy evaluation of radioimmunotherapy with 90Y‐labeled anti‐podoplanin antibody NZ‐12 for mesothelioma

“…Pemetrexed is recommended as first‐line chemotherapy for malignant mesothelioma and is the first candidate as a radiosensitizer with RIT against mesothelioma. Third, repeated dosing with intact NZ‐12 after RIT could enhance the therapeutic effect because NZ‐12 is reported to induce potent antibody‐dependent cellular cytotoxicity against podoplanin‐expressing tumors . NZ‐12 is a chimeric antibody and is expected to have a low risk of immunogenicity, suggesting that NZ‐12 is suitable for repeated dosing over a long period of time.…”

“…We previously developed a rat-human chimeric anti-podoplanin antibody, NZ-12, which has high specificity and high binding affinity for podoplanin expressed on mesothelioma cells. 30,31 In the present study, the potential of radiolabeled NZ-12 as a RIT agent was evaluated in a mesothelioma mouse model.…”

“…To address this concern, it is important to select an antibody that recognizes podoplanin expressed on cancer cells only and not on normal cells. We developed a rat anti‐podoplanin monoclonal antibody, NZ‐1, which has the above‐mentioned property, and converted it to a rat‐human chimeric antibody named NZ‐12 . These antibodies recognize podoplanin expressed on the surface of cancer cells, such as brain tumor, lung cancer, and malignant mesothelioma, but not in benign tumor cells or normal organs .…”

“…We developed a rat anti-podoplanin monoclonal antibody, NZ-1, which has the above-mentioned property, 29 and converted it to a rat-human chimeric antibody named NZ-12. 30 These antibodies recognize podoplanin expressed on the surface of cancer cells, such as brain tumor, lung cancer, and malignant mesothelioma, but not in benign tumor cells or normal organs. 19,31 Therefore, NZ-12 has potential application for selective antitumor therapy including RIT against malignant mesothelioma.…”

Podoplanin promotes progression of malignant pleural mesothelioma by regulating motility and focus formation

“…Podoplanin is a diagnostic marker for MPM and it promotes the progression of MPM, so PDPN could potentially serve as a therapeutic target. Over the past few years, anti‐PDPN antibodies that inhibit platelet aggregation and mediate antibody‐dependent cellular cytotoxicity (ADCC) have been created to target PDPN . Agents that target PDPN should prove effective in treating MPM.…”