Abstract
Podoplanin (Aggrus), which is a type I transmembrane sialomucin-like glycoprotein, is highly expressed in malignant pleural mesothelioma (MPM). We previously reported the generation of a rat anti-human podoplanin Ab, NZ-1, which inhibited podoplanin-induced platelet aggregation and hematogenous metastasis. In this study, we examined the antitumor effector functions of NZ-1 and NZ-8, a novel rat-human chimeric Ab generated from NZ-1 including Ab-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity against MPM in vitro and in vivo. Immunostaining with NZ-1 showed the expression of podoplanin in 73% (11 out of 15) of MPM cell lines and 92% (33 out of 36) of malignant mesothelioma tissues. NZ-1 could induce potent ADCC against podoplanin-positive MPM cells mediated by rat NK (CD161a(+)) cells, but not murine splenocytes or human mononuclear cells. Treatment with NZ-1 significantly reduced the growth of s.c. established tumors of MPM cells (ACC-MESO-4 or podoplanin-transfected MSTO-211H) in SCID mice, only when NZ-1 was administered with rat NK cells. In in vivo imaging, NZ-1 efficiently accumulated to xenograft of MPM, and its accumulation continued for 3 wk after systemic administration. Furthermore, NZ-8 preferentially recognized podoplanin expressing in MPM, but not in normal tissues. NZ-8 could induce higher ADCC mediated by human NK cells and complement-dependent cytotoxicity as compared with NZ-1. Treatment with NZ-8 and human NK cells significantly inhibited the growth of MPM cells in vivo. These results strongly suggest that targeting therapy to podoplanin with therapeutic Abs (i.e., NZ-8) derived from NZ-1 might be useful as a novel immunotherapy against MPM.
Highlights
Treatment with NZ-8 and human NK cells significantly inhibited the growth of malignant pleural mesothelioma (MPM) cells in vivo. These results strongly suggest that targeting therapy to podoplanin with therapeutic Abs (i.e., NZ-8) derived from NZ-1 might be useful as a novel immunotherapy against MPM
We have demonstrated that a rat anti-human podoplanin mAb, NZ-1, possesses potent Ab-dependent cellular cytotoxicity (ADCC) mediated by rat NK cells and complement-dependent cytotoxicity (CDC) activity and mediates in vivo therapeutic antitumor activity against MPM in SCID mice
We have shown that a novel rat-human chimeric anti-human podoplanin Ab, NZ-8, effectively induces ADCC mediated by human NK cells and CDC and mediates in vivo antitumor activity against MPM cells
Summary
NZ-1 could induce potent ADCC against podoplanin-positive MPM cells mediated by rat NK (CD161a+) cells, but not murine splenocytes or human mononuclear cells. Significant ADCC against only podoplanin-positive, but not podoplanin-negative, MPM cells was induced by NZ-1 when splenocytes of Wistar rat were used as effector cells (Fig. 2C). NZ-1 effectively induced ADCC against podoplanin-expressing cells in a dose- and time-dependent manner (Fig. 2F, 2G).
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