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

Abstract

Podoplanin is a type I transmembrane sialomucin‐like glycoprotein that is highly expressed in malignant mesothelioma. The rat‐human chimeric antibody NZ ‐12 has high affinity for human podoplanin and antibody‐dependent cellular cytotoxicity and is applicable for radioimmunotherapy ( RIT ) to enhance the antitumor effect. In the present study, we evaluated the in vivo and in vitro properties of radiolabeled NZ ‐12 and the antitumor effect of RIT with 90 Y‐labeled NZ ‐12 in an NCI ‐H226 (H226) malignant mesothelioma xenograft mouse model. 111 In‐labeled NZ ‐12 bound specifically to H226 cells with high affinity, and accumulation was high in H226 tumors but low in major organs. RIT with 90 Y‐labeled NZ ‐12 significantly suppressed tumor growth and prolonged survival without body weight loss and obvious adverse effects. Higher podoplanin expression levels were observed in human mesothelioma specimens, suggesting higher tumor accumulation of 90 Y‐labeled NZ ‐12 in patients compared with the H226 tumor xenografts. Our findings suggest that 90 Y‐labeled NZ ‐12 is a promising RIT agent as a new therapeutic option for malignant mesothelioma that warrants further clinical studies to evaluate the dosimetry and efficacy in patients.

Preclinical Evaluation of Podoplanin-Targeted Alpha-Radioimmunotherapy with The Novel Antibody NZ-16 for Malignant Mesothelioma

“…Therefore, RIT with NZ-16 was expected to be more effective and NZ-16 was selected for further evaluation. As expected, 90 Y-and 225 Ac-labeled NZ-16 showed significant antitumor effects in tumor-bearing mice, compared with 90 Y-labeled NZ-12 [15]. The significantly higher effectiveness of 225 Ac-labeled NZ-16 compared with 90 Y-labeled NZ-16 (P < 0.01) suggests that a-RIT with NZ-16 is a promising therapy for malignant mesothelioma.…”

“…The treatment with 225 Ac-labeled NZ-16 was markedly more effective than that with 90 Ylabeled NZ-16, suggesting that the real RBE is greater than 5.7. To estimate the RBE by another method, we referred to the results of X-ray treatment against H226 tumors in a previous report [15]. The efficacy of 11.1 kBq of 225 Ac-labeled NZ-16 was almost equivalent to that of 50 Gy of X-ray radiation, and the RBE was calculated to be 19.2 for 225 Ac relative to X-rays.…”

“…A previous study reported that 90 Y-labeled anti-PDPN antibody NZ-12 suppresses tumor growth in a mesothelioma model cell line NCI-H226 (H226); unfortunately, complete remission was not achieved [15]. To improve the therapeutic effect of RIT with an anti-PDPN antibody, we newly developed an anti-PDPN antibody, NZ-16, having a different constant region than NZ-12.…”

Preclinical Evaluation of Podoplanin-Targeted Alpha-Radioimmunotherapy with the Novel Antibody NZ-16 for Malignant Mesothelioma

“…An anti-PDPN antibody, NZ-16, was newly developed from the parental antibody NZ-1. The constant region of the NZ-16 heavy chain differs from that in NZ-12, which was evaluated as a radioimmunotherapeutic agent in a previous study [6]. NZ-16 has a higher affinity and showed higher tumor uptake in a PDPN-expressing H226 mesothelioma mouse model than NZ-12.…”

Targeted Phototherapy for Malignant Pleural Mesothelioma: Near-Infrared Photoimmunotherapy Targeting Podoplanin

“…There are interesting approaches to treat cancers with antibodies [43]. Firstly, the effect of radioimmunotherapy (RIT) using the rat-human chimeric antibody NZ-12 has been reported [44]. NZ-12 is applicable for RIT and radiolabeled NZ-12 enhances the antitumor effect.…”