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131I标记的人源化抗B7-H3抗体用于胶质母细胞瘤放射免疫疗法的治疗特性 Article
傅丰庆, Meng Zheng, Shandong Zhao, Yan Wang, Minzhou Huang, Hanqing Chen, Ziyi Huang, Kaijie Zhang, 缪丽燕, 张学光
《工程（英文）》 2023年 第30卷 第11期 页码 190-202 doi: 10.1016/j.eng.2023.05.011
B7 homolog 3 (B7-H3) has attracted much attention in glioblastoma (GBM) radioimmunotherapy (RIT) due to its abnormally high expression on tumor cells. In this study, we report that two specific humanized anti-human B7-H3 antibodies (hu4G4 and hu4H12) derived from mouse anti-human B7-H3 antibodies that were generated by computer-aided design and exclusively recognize membrane expression of B7-H3 by human glioma cells. Hu4G4 and hu4H12 were radiolabeled with 89Zr for RIT antibody screening. Micro-positron emission tomography (PET) imaging, biodistribution and pharmacokinetic (PK) analyses of 89Zr-labeled antibodies were performed in U87-xenografted models. 125I labelling of the antibodies for single-photon emission computed tomography (SPECT) imaging was also used to investigate the biological behavior of the antibodies in vivo. Furthermore, the pharmacodynamic (PD) of the 131Ilabeled antibodies were evaluated in U87-xenografted mice and GL261 Red-FLuc-B7-H3 in situ glioma tumor models. Micro-PET imaging and biodistribution analysis with a gamma counter showed that 89Zr-deferoxamine (DFO)-hu4G4 had higher tumor targeting performance with lower liver uptake than 89Zr-DFO (hu4H12, immunoglobulin G (IgG)). The biodistribution results of 125I-SPECT imaging were similar to those of 89Zr-PET imaging, though the biodistribution in long bone joints and the thyroid varied. The PD analysis results indicated that 131I-hu4G4 had an excellent therapeutic effect and high safety with no apparent toxicity. Interestingly, 131I-hu4G4 improved the tumor vasculature in tissues with higher expression of collagen type IV and platelet-derived growth factor receptor b (PDGFR-b) compared with control treatment, as determined by immunofluorescence (IF), which contributed to inhibiting tumor growth. Taken together, our data indicate that hu4G4 exhibits good tumor targeting and specificity, achieves low nonspecific concentrations in normal tissues, and has acceptable PK characteristics. 131I-hu4G4 also exerts effective antitumor effects with an ideal safety profile. Therefore, we expect hu4G4 to be an excellent antibody for the development of GBM RIT.
关键词： B7-H3 Radioimmunotherapy Glioblastoma Pharmacokinetics Pharmacodynamics
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