Therapeutic Characterization of ^(131)I-Labeled Humanized Anti-B7-H3 Antibodies for Radioimmunotherapy for Glioblastoma  

作　　者：Fengqing Fu Meng Zheng Shandong Zhao Yan Wang Minzhou Huang Hanqing Chen Ziyi Huang Kaijie Zhang Liyan Miao Xueguang Zhang 

机构地区：[1]Jiangsu Institute of Clinical Immunology,the First Affiliated Hospital of Soochow University,Suzhou 215000,China [2]State Key Laboratory of Radiation Medicine and Protection,Soochow University,Suzhou 215123,China [3]Department of Clinical Pharmacology,the First Affiliated Hospital of Soochow University,Suzhou 215006,China [4]Suzhou Bright Scistar Antibody Biotech.Co.,Ltd.,Suzhou 215152,China [5]Institute for Interdisciplinary Drug Research and Translational Sciences,College of Pharmaceutical Sciences,Soochow University,Suzhou 215123,China [6]Department of Hematology,the First Affiliated Hospital of Soochow University,Suzhou 215000,China

出　　处：《Engineering》2023年第11期190-202,共13页工程（英文）

基　　金：funded by the National Natural Science Foundation of China(31320103918 and 82104318);Key Research and Development Program of Jiangsu Province(BE2021644);the Jiangsu Innovative and Entrepreneurial Talent Programme(JSSCBS20211568);the Science and Technology Plan of Suzhou(SKJYD2021161 and SKY2022046);Key Project of Jiangsu Provincial Health Commission(zd2021050);the Project of State Key Laboratory of Radiation Medicine and Protection,Soochow University(GZK1202203);support of Jiangsu Institute of Nuclear Medicine for the ^(89)Zr-PET imaging in this study。

摘　　要：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^(89)Zr for RIT antibody screening.Micro-positron emission tomography(PET)imaging,biodistribution and pharmacokinetic(PK)analyses of^(89)Zr-labeled antibodies were performed in U87-xenografted models.^(125)I 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.Fu rthermore,the pharmacodynamic(PD)of the^(131)Ilabeled 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^(89)Zr-deferoxamine(DFO)-hu4G4 had higher tumor targeting performance with lower liver uptake than^(89)Zr-DFO-(hu4H12,immunoglobulin G(IgG)).The biodistribution results of^(125)I-SPECT imaging were similar to those of^(89)Zr-PET imaging,though the biodistribution in long bone joints and the thyroid varied.The PD analysis results indicated that^(131)I-hu4G4 had an excellent therapeutic effect and high safety with no apparent toxicity.Interestingly,^(131)I-hu4G4 improved the tumor vasculature in tissues with higher expression of collagen typeⅣand platelet-derived growth factor receptorβ(PDGFR-β)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.^(131)I-hu4G4 also exerts effective antitumor effects with an ideal safety p

关 键 词：B7-H3 RADIOIMMUNOTHERAPY GLIOBLASTOMA PHARMACOKINETICS PHARMACODYNAMICS 

分 类 号：R739.4[医药卫生—肿瘤]