Purpose This study aimed to evaluate the potential of podoplanin (PDPN)-targeted alpharadiotherapy (RIT) for treating malignant mesothelioma.Methods A newly developed anti-PDPN antibody, NZ-16, and a previous anti-PDPN antibody, NZ-12, were assessed. The in vitro properties of radiolabeled antibodies were evaluated by cell binding and competitive inhibition assays using PDPN-expressing NCI-H226 (H226) mesothelioma cells. The biodistribution of 111 In-labeled antibodies was studied in

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... g mice. Tumor volumes and body weights of mice treated with 90 Y- and 225 Ac-labeled NZ-16 were measured for 56 days. The absorbed doses were estimated on the basis of the biodistribution data. Pathologic analysis of tumors and organs was conducted.Results The radiolabeled NZ-16 specifically bound to H226 cells with higher affinity than NZ12. The biodistribution studies showed higher tumor uptake of radiolabeled NZ-16 compared with NZ-12. RIT with 225 Ac-labeled NZ-16 (11.1 and 18.5 kBq) had a significantly higher antitumor effect than RIT with 90 Y-labeled NZ-16 (3.7 MBq; P < 0.01). 225 Ac-labeled NZ-16 induced more necrosis compared with 90 Y-labeled NZ-16, but the Ki-67 index and apoptosis rate were similar. The estimated absorbed doses were expected to be tolerable in mice. Temporary body weight loss occurred, but recovered within several days. No visible damage to major organs was detected.Conclusion The novel anti-PDPN antibody NZ-16 was a more effective RIT agent than NZ12. Radiolabeled NZ-16, especially 225 Ac-labeled NZ-16, markedly suppressed tumor growth and prolonged survival without inducing severe adverse effects. RIT with radiolabeled NZ-16 is a promising therapeutic option for malignant mesothelioma.