Antibody-Drug Conjugate to Treat Meningiomas.

Kai Chen,Patrick Ernst,Xiaosi Han,Xiaoguang (Margaret) Liu,Seulhee Kim,Jianfa Ou,Ya Zhang,Lufang Zhou,Yingnan Si,Jia-Shiung Guan

doi:10.3390/ph14050427

Kai Chen, Patrick Ernst + Show 8 more

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https://doi.org/10.3390/ph14050427

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Abstract

Meningiomas are primary tumors of the central nervous system with high recurrence. It has been reported that somatostatin receptor 2 (SSTR2) is highly expressed in most meningiomas, but there is no effective targeted therapy approved to control meningiomas. This study aimed to develop and evaluate an anti-SSTR2 antibody–drug conjugate (ADC) to target and treat meningiomas. The meningioma targeting, circulation stability, toxicity, and anti-tumor efficacy of SSTR2 ADC were evaluated using cell lines and/or an intracranial xenograft mouse model. The flow cytometry analysis showed that the anti-SSTR2 mAb had a high binding rate of >98% to meningioma CH157-MN cells but a low binding rate of <5% to the normal arachnoidal AC07 cells. The In Vivo Imaging System (IVIS) imaging demonstrated that the Cy5.5-labeled ADC targeted and accumulated in meningioma xenograft but not in normal organs. The pharmacokinetics study and histological analysis confirmed the stability and minimal toxicity. In vitro anti-cancer cytotoxicity indicated a high potency of ADC with an IC50 value of <10 nM. In vivo anti-tumor efficacy showed that the anti-SSTR2 ADC with doses of 8 and 16 mg/kg body weight effectively inhibited tumor growth. This study demonstrated that the anti-SSTR2 ADC can target meningioma and reduce the tumor growth.

Highlights

Our study showed that the anti-somatostatin receptor 2 (SSTR2) antibody–drug conjugate (ADC) can effectively target meningioma and inhibit the tumor proliferation with minimal toxicity
We constructed and evaluated the SSTR2-targeting ADC for meningioma treatment using our previously developed anti-human and mouse SSTR2 mAbs (IgG1 kappa) that targets the extracellular domain of SSTR2 [39]
This study has developed and evaluated an anti-SSTR2 monoclonal antibody–drug conjugate for meningioma-targeted therapy

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Meningiomas are the most common primary tumors in the central nervous system. Malignant meningiomas have overall five-year survival rates of 64.6–68.5% due to the greater recurrence rate and mortality as reported by the Central Brain Tumor Registry of the United States (CBTRUS) 2020 [1]. A significant subset of meningiomas (WHO grade II and III) have aggressive features and are associated with uncontrollable growth and high rates of morbidity and mortality [2,3]. The tumors contain widespread genomic disruption (amplification, deletion, and rearrangement), inactivation of neurofibromatosis type 2 (NF2)

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