並列タイトル等抗ポドプラニン抗体はナチュラルキラー細胞による悪性中皮腫に対する抗CTLA-4抗体の抗腫瘍効果を増強する
一般注記Combination immunotherapy with multiple immune checkpoint inhibitors (ICIs) has been approved for various types of malignancies, including malignant pleural mesothelioma (MPM). Podoplanin (PDPN), a transmembrane sialomucin-like glycoprotein, has been investigated as a diagnostic marker and therapeutic target for MPM. We previously generated and developed a PDPN-targeting Ab reagent with high Ab-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). However, the effects of anti-PDPN Abs on various tumor-infiltrating immune cells and their synergistic effects with ICIs have remained unclear. In the present study, we established a novel rat–mouse chimeric anti- mouse PDPN IgG2a mAb (PMab-1-mG2a) and its core-fucose-deficient Ab (PMab-1-mG2a-f) to address these limitations. We identified the ADCC and CDC activity of PMab-1-mG2a-f against the PDPN-expressing mesothelioma cell line AB1-HA. The antitumor effect of monotherapy with PMab-1-mG2a-f was not sufficient to overcome tumor progression in AB1-HA-bearing immunocompetent mice. However, PMab-1-mG2a-f enhanced the antitumor effects of CTLA-4 blockade. Combination therapy with anti-PDPN Ab and anti-CTLA-4 Ab increased tumor-infiltrating natural killer (NK) cells. The depletion of NK cells inhibited the synergistic effects of PMab-1-mG2a-f and CTLA-4 blockade in vivo. These findings indicated the essential role of NK cells in novel combination immunotherapy targeting PDPN and shed light on the therapeutic strategy in advanced MPM.
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連携機関・データベース国立情報学研究所 : 学術機関リポジトリデータベース(IRDB)(機関リポジトリ)