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

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Engineering 2023年第11期30卷 190-202页

作者： Fengqing Fu Meng Zheng Shandong Zhao Yan Wang Minzhou Huang Hanqing Chen Ziyi Huang Kaijie Zhang Liyan Miao Xueguang Zhang Jiangsu Institute of Clinical Immunology the First Affiliated Hospital of Soochow UniversitySuzhou 215000China State Key Laboratory of Radiation Medicine and Protection Soochow UniversitySuzhou 215123China Department of Clinical Pharmacology the First Affiliated Hospital of Soochow UniversitySuzhou 215006China Suzhou Bright Scistar Antibody Biotech.Co. Ltd.Suzhou 215152China Institute for Interdisciplinary Drug Research and Translational Sciences College of Pharmaceutical SciencesSoochow UniversitySuzhou 215123China Department of Hematology the First Affiliated Hospital of Soochow UniversitySuzhou 215000China

B7 homolog 3(B7-H3)has attracted much attention in glioblastoma(GBM)radioimmunotherapy(RIT)due to its abnormally high expression on tumor *** 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 ***-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 *** 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 ***-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 *** PD analysis results indicated that^(131)I-hu4G4 had an excellent therapeutic effect and high safety with no apparent ***,^(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 *** 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 effect

关键词： B7-H3 radioimmunotherapy Glioblastoma Pharmacokinetics Pharmacodynamics

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Tellurium-driven maple leaf-shaped manganese nanotherapeutics reshape tumor microenvironment via chemical transition in situ to achieve highly efficient radioimmunotherapy of triple negative breast cancer

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Bioactive Materials 2023年第9期27卷 560-573页

作者： Wei Huang Sujiang Shi Haoran Lv Zhenyu Ju Qinghua Liu Tianfeng Chen Jieyang Medical Research Center Jieyang People’s HospitalTianfu Road 107Rongcheng DistrictJieyangGuangdong522000China Department of Nephrology The First Affiliated HospitalNHC Key Laboratory of Clinical Nephrology(Sun Yat-Sen University)and Guangdong Provincial Key Laboratory of NephrologySun Yat-sen UniversityGuangzhouChina Key Laboratory of Regenerative Medicine of Ministry of Education Institute of Aging and Regenerative MedicineJinan UniversityGuangzhou510632China Department of Chemistry Jinan UniversityGuangzhou510632China

The therapeutic efficacy of radioimmunotherapy against triple negative breast cancer(TNBC)is largely limited by the complicated tumor microenvironment(TME)and its immunosuppressive *** developing a strategy to reshape TME is expected to achieve highly efficient ***,we designed and synthesized a tellurium(Te)-driven maple leaf manganese carbonate nanotherapeutics(MnCO3@Te)by gas diffusion method,but also provided a chemical catalytic strategy in situ to augment ROS level and activate immune cells for improving cancer *** expected,with the help of H2O2 in TEM,MnCO3@Te heterostructure with reversible Mn3+/Mn2+transition could catalyze the intracellular ROS overproduction to amplify *** addition,by virtue of the ability to scavenge H+in TME by carbonate group,MnCO3@Te directly promote the maturation of dendritic cells and macrophage M1 repolarization by stimulator of interferon genes(STING)pathway activation,resulting in remodeling *** a result,MnCO3@Te synergized with radiotherapy and immune checkpoint blockade therapy effectively inhibited the breast cancer growth and lung metastasis in ***,these findings indicate that MnCO3@Te as an agonist,successfully overcome radioresistance and awaken immune systems,showing promising potential for solid tumor radioimmunotherapy.

关键词： radioimmunotherapy Triple negative breast cancer Tellurium Manganese carbonate Tumor microenvironment

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Therapeutic dendritic cell vaccines engineered with antigen-biomineralized Bi_(2)S_(3) nanoparticles for personalized tumor radioimmunotherapy

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Aggregate 2022年第5期3卷 227-237页

作者： Huan Yu Haoxiang Guo He Zu Heng Ding Subin Lin Yangyun Wang Leshuai W Zhang Yong Wang State Key Laboratory of Radiation Medicine and Protection School of Radiation Medicine and ProtectionCollaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education InstitutionsSoochow UniversitySuzhouChina Department of Orthopedic The Second Affiliated Hospital of Soochow UniversitySuzhouChina

Therapeutic vaccines,an exciting development in cancer immunotherapy,share the goal of priming of personalized antigen-specific T-cell response by precise antigen presentation of dendritic cells(DCs),but major obstacles include insufficient antigen loading and off-target to DCs remain to their ***,we developed an imageable therapeutic vaccine with whole-antigen loading and target delivery constructed by ovalbumin(OVA)-biomineralized Bi_(2)S_(3) nanoparticles-pulsed *** on the strong X-ray absorption and fluorescence labeling performance of Bi_(2)S_(3)@OVA nanoparticles,the in vivo spatiotemporal fate of the vaccine(Bi_(2)S_(3)@OVA@DC)can be noninvasively monitored by computed tomography and near-infrared fluorescence imaging in real *** Bi_(2)S_(3)@OVA@DC can rapidly and durably accumulate in draining lymph nodes and thus trigger stronger T-cell responses compared to OVA-pulsed ***,Bi_(2)S_(3)@OVA@DC can further achieve in vivo antitumor effects against OVA-expressing B16F10 melanoma when combined with fractionated radiotherapy,resulting from the upregulation of cytotoxic CD8^(+)T cells and restraint of regulatory T cells in the tumor microenvironment,and the systemical secretion of OVA-specific IgG1/IgG2α ***,we successfully fabricated an engineered DC vaccine featured in high whole-antigen loading capacity that can be precisely delivered to the lymphatic system for visualization,serving as a powerful therapeutic platform for cancer radioimmunotherapy.

关键词： antigen-biomineralized Bi_(2)S_(3)nanoparticles dendritic cells radioimmunotherapy therapeutic vaccines visualization

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radioimmunotherapy of carcinoma of colon with [131I]-labeled recombinant chimeric monoclonal antibodies to carcinoembryonic antigen

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Acta Pharmacologica Sinica 2005年第10期26卷 1259-1264页

作者： Qiu-jun LU~1, Guang-xing BIAN, Yuan-yuan CHEN, Min ZHANG, Shao-ming GUO, Li-qing WEN Institute of Radiation Medicine, Beijing 100850, China Institute of Radiation Medicine Beijing China

Aim: To study the distribution of [131I]-labeled anti-CEA MoAbs and its therapeutic effect on the human colonic cancer model in nude mice. Methods: A nude mice model of human colonic cancer was established. [~131I]-labeled anti-CEA MoAbs were injected intravenously into mice. The distribution of the MoAbs was then determined and the effect of RIT on human colonic cancer was observed. Results: The [131I]-labeled anti-CEA MoAbs had a specific distribution after injection. Tumor/non-tumor ratios for [131I]-labeled anti-CEA MoAbs were 10-20 times higher than [131I]-labeled IgG 96 h after injection. Thirty days after injection, significant inhibition of the volume and weight of tumor was observed in the treated mice compared with the control. The tumor growth inhibition rate of 3,1 mCi/kg CEA MoAbs group (LS180, LS174T, SW1116) was 47.8%～64.0%. This was 69.6%-78.6% in the 6.25 mCi/kg CEA MoAbs group, and 81.8%-86.2% in the 12.5 mCi/kg [131I]-labeled anti-CEA MoAbs group. The plasma CEA level was alo lower in treated mice. Conclusion: The results indicate that [131I]-labeled anti-CEA MoAbs can be effective in RIT on colonic cancers.

关键词： humanized chimeric recombinant monoclonal antibody radioimmunotherapy colonic cancer nude mice

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radioimmunotherapy　IN　TREATMENT　OF　UNRESECTABLE　HEPATOMA－A　REPORT　OF　43　CASES

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Chinese Journal of Cancer Research 1994年第1期6卷 74-78页

作者：刘康达汤钊猷范桢陆继珍余业勤周信达 Liver Cancer Institute Shanghai Medical University Shanghai

Forty-three patients with surgically verified unresectable hepatoma had been treated by radioimmunotherapy(RIT)using￣(131)I antiferritin antibidy as a part of multimodality treatment during 1985 - *** shortand long-term responses were compared with those in control group of 39 patients with unresectable hepatoma receiving conventional multimodality treatment in the same *** rates of the tumor shrinkage,serum AFP decline and sequence resction were 67. 4% (29/43),69.6%(16/23)and 30.2%(13/43)respectively,which were significantly higher than those in contrul group[23.1%(15/39),40.0%(8/20)and 10.3%(4/39),respectively].The 1-,3- and 5-year survival rates were 61.5%,40.4%and 35.4%,respectively,for the RIT group,and 51.2%,20.1% and 15.5% ,respectrely,for the control *** tumor size,dose of RIT and sequence resection were identified as significant factors (P=0.005,0.025 and 0.006,respectively, with Cox analysis model in 13 influencing *** results indicate that RIT was an effective one in multimodality treatment,particularly in the conversion of unresectable to resectable tumor.

关键词： radioimmunotherapy Multimodality treatment Hepatoma Sequence resection.

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Near-Infrared Light-Responsive Nitric Oxide Delivery Platform for Enhanced radioimmunotherapy

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Nano-Micro Letters 2020年第8期12卷 116-129页

作者： Xuanfang Zhou Zhouqi Meng Jialin She Yaojia Zhang Xuan Yi Hailin Zhou Jing Zhong Ziliang Dong Xiao Han Muchao Chen Qin Fan Kai Yang Chao Wang Institute of Functional Nano and Soft Materials(FUNSOM) Jiangsu Key Laboratory for Carbon-Based Functional Materials and DevicesSoochow UniversitySuzhou 215123JiangsuPeople’s Republic of China State Key Laboratory of Radiation Medicine and Protection School of Radiation Medicine and Protection and School for Radiological and Interdisciplinary Sciences(RAD-X)Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education InstitutionsSoochow UniversitySuzhou 215123JiangsuPeople’s Republic of China

Radiotherapy(RT)is a widely used way for cancer ***,the efficiency of RT may come with various challenges such as low specificity,limitation by resistance,high dose and so *** oxide(NO)is known a very effective radiosensitizer of hypoxic ***,NO cannot circulate in body with high ***,an NIR light-responsive NO delivery system is developed for controlled and precisely release of NO to hypoxic tumors during ***-Butyl nitrite,which is an efficient NO source,is coupled to Ag2S quantum dots(QDs).NO could be generated and released from the Ag2S QDs effectively under the NIR irradiation due to the thermal *** addition,Ag is also a type of heavy metal that can benefit the RT *** demonstrate that Ag2S NO delivery platforms remarkably maximize radiotherapy effects to inhibit tumor growth in CT26 tumor ***,immunosuppressive tumor microenvironment is improved by our NO delivery system,significantly enhancing the anti-PD-L1 immune checkpoint blockade therapy.100% survival rate is achieved by the radio-immune combined therapy strategy based on the Ag2S NO delivery *** results suggest the promise of Ag2S NO delivery platforms for multifunctional cancer radioimmunotherapy.

关键词： NO delivery Radio sensitivity Multifunctional agent radioimmunotherapy Drug delivery

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Fractionated radioimmunotherapy using low doses of iodine 131 labeled anti-CEA monoclonal antibody after tumor volume reduction

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Chinese Medical Journal 2000年第1期113卷 53-58页

作者：田嘉禾丁勇张锦明曹丽敏尹大一 Department of Nuclear Medicine Great Wall Hospital Beijing 100853 China Department of Nuclear Medicine Chinese PLA General Hospital Beijing 100853 China

OBJECTIVE: To assess the efficacy of fractionated administration of radiolabeled monoclonal antibody in the treatment of metastases after tumor volume reduction surgery, various experimental therapies were studied comparatively. METHODS: A total of 200 inbred mice received tumor implantation from a murine adenocarcinoma cell line. The mice were randomly grouped to give saline, Arc-a, 131I-C50 in single or fractionated doses, cold C50, or non-specific 131I-IgG with or without surgical removal of the implanted tumor xenograft. RESULTS: In comparison to controls, animals receiving Arc-a and radioactive agents had longer survival, smaller tumor, better clinical condition, and less metastases foci. The best therapeutic response was noted after fractionated doses of 131I-C50, which showed better results in every aspect than those treated with other modalities. The favorable outcome was even more pronounced after tumor volume reduction. CONCLUSIONS: Fractionated dosing may improve the deposition of radiolabeled monoclonal antibody (McAb) and provide the best therapeutic effect on implanted tumor and metastases. Thus fractionated radioimmunotherapy (RIT) after tumor volume reduction might be a practical method with promising therapeutic results.

关键词： radioimmunotherapy Animals Antibodies, Monoclonal Body Weight Carcinoembryonic Antigen Dose Fractionation Iodine Radioisotopes Mice Mice, Inbred Strains Neoplasm Metastasis Neoplasms, Experimental Radiotherapy Dosage

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Combined treatment of pancreatic cancer xenograft with 90Y-ITGA6B4-mediated radioimmunotherapy and PI3K/m TOR inhibitor

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World Journal of Gastroenterology 2017年第42期23卷 7551-7562页

作者： Winn Aung Atsushi B Tsuji Hitomi Sudo Aya Sugyo Yoshinori Ukai Katsushi Kouda Yoshikazu Kurosawa Takako Furukawa Tsuneo Saga Tatsuya Higashi Department of Molecular Imaging and Theranostics National Institute of Radiological SciencesNational Institutes for Quantum and Radiological Science and Technology(QST-NIRS) Perseus Proteomics Inc. Innovation Center for Advanced Medicine Fujita Health University Department of Radiological and Medical Laboratory Sciences Nagoya University Graduate School of Medicine Department of Diagnostic Radiology Kyoto University Hospital

AIM To investigate the therapeutic effect of combined integrin α6β4-targeted radioimmunotherapy(RIT) and PI3 K/m TOR inhibitor BEZ235 in a pancreatic cancer *** Phosphorylation of Akt, m TOR, the downstream effectors eukaryotic initiation factor 4 E binding protein 1(4 EBP1) and S6 ribosomal protein(S6) were evaluated in Bx PC-3 human pancreatic cancer cells treated with Yttrium-^(90)(^(90) Y) labeled anti-integrin α6β4 antibody(ITGA6 B4) and BEZ235 by western blotting. The cytotoxic effect of BEZ235 was investigated using a colony formation assay. Therapeutic efficacy enhancement by oral BEZ235 administration was assessed using mice bearing Bx PC-3 xenograft tumors. Tumor volume measurements and immunohistochemical analyses(cell proliferation marker Ki-67, DNA damage marker p-H2 AX and p-4 EBP1 staining) of tumors were performed for evaluation of combined treatment with ^(90) Y-ITGA6 B4 plus BEZ235, or each arm *** We found that phosphorylation of Akt(p-Akt), 4 EBP1(p-4 EBP1) and S6(p-S6) was inhibited by BEZ235. Colony formation in Bx PC-3 cells was additively suppressed by the combination of ^(90) Y-ITGA6 B4 and BEZ235. Pretreatment with BEZ235 before ^(90) Y-ITGA6 B4 exposure resulted in significant reduction of cells plating efficiency(PE)(0.54 ± 0.11 vs 2.81 ± 0.14 with 185 k Bq/m L ^(90) Y-ITGA6 B4 exposure, P < 0.01; 0.39 ± 0.08 vs 1.88 ± 0.09 with 370 k Bq/m L ^(90) Y-ITGA6 B4 exposure, P < 0.01) when 5 × 10~3 cells per dish were plated. In vivo, the combined treatment with ^(90) Y-ITGA6 B4 plus BEZ235 enhanced the inhibition of tumor growth and statistically significant differences of relative tumor volume were observed for 27 d after the treatment start date when compared with the ^(90) Y-ITGA6 B4 single injection treatment(1.03 ± 0.38 vs 1.5 ± 0.15 at Day 27, P < 0.05), and for 41 d when compared with the BEZ235 treatment alone(1.8 ± 0.7 vs 3.14 ± 1.19 at Day 41, P < 0.05). Tumors from treatment groups showed reduction in volumes, dec

关键词： radioimmunotherapy Pancreatic cancer Anti-integrin α6β4 antibody Yttrium-90 NVP-BEZ235

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CHANGES　OF　SERUM　ALPHA　FETOPROTEIN　BEFORE　AND　AFTER　radioimmunotherapy　IN　PATIENTS　WITH　HEPATOCELLULAR　CARCINOMA

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Chinese Journal of Cancer Research 1994年第2期6卷 83-90页

作者：曾昭冲汤钊猷 Liver Cancer Institute Shanghai Medical University Shanghai

Thirtytwo patients with surgically verified unresectable table hepatocellular carcinoma (HCC) have been treated by radioimmunotherapy (RIT) using intrahepatic arterial administration of￣(131)I anti HCC monoclonal antibody (Hepama1) combined with hepetic artery ligation. Twenty of them had abnormal serum alpha fetoprotein (AFP,>20 ng/ml). Single photon emission computed tomography (SPECT) scan and quantitative assay of AFP were performed after RIT. The results revealed that when the tumor to liver ratio (T/L) was higher than 3.5 (Group A , n =3) , the serum AFP level declined markedly and then kept in stable for a tongtime; when the T/L ratio was less than 1.2 (Group C ,n=5), the serum AFP level did not change evidently within 2 months postinfusion; while the T/L ratio was between 1. 2 3. 5 (Group B, n= 12) , the serum AFP level increased transiently and then decreased within 2 4 weeks postinfusion. Sequentiat resection was achieved in all of the 3 patients of Group A, in 6 patients (50%) of Group B, and none in Group C. The correlation of serum AFP and effective treatment demonstrates the usefulness of this oncofetal protein marker as an indicator of neoplastic activity for HCC and T/L ratio might be a good indicator to predict tumor response to RIT in patients with

关键词： radioimmunotherapy Alpha fetoprotein,Hepatoma Monoclonal antibody Proliferation.

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Screening for a^(177)Lu-labeled CA19–9 monoclonal antibody via PET imaging for colorectal cancer therapy

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Chinese Chemical Letters 2022年第7期33卷 3502-3506页

作者： Jing Wang Liangang Zhuo Peng Zhao Wei Liao Hongyuan Wei Yuchuan Yang Shuming Peng Xia Yang Institute of Nuclear Physics and Chemistry China Academy of Engineering PhysicsMianyang 621900China NHC Key Laboratory of Nuclear Technology Mediccal Trasnformation(Mianyang Central Hospital) Mianyang 621900China Key Laboratory of Nuclear Medicine and Molecular Imaging of Sichuan Province Mianyang 621999China Department of Nuclear Medicine The Affiliated Hospital Southwest of Medical UniversityLuzhou 646000China

Carbohydrate antigen 19–9(CA19–9)with multi epitopes relatively high expresses on colorectal cancer(CRC)cells,making it an attractive target for developing radioimmunotherapy(RIT)for *** lutetium-177(^(177)Lu)labeled monoclonal antibodies(mA bs)can selectively bind the corresponding antigens and release targeted cytotoxic radiation,which could induce cell apoptosis and reduce the drug-induced ***,a series of CA19–9 m Abs were labeled with zirconium-89(^(89)Zr),and one with high tumor uptake was screened via PET imaging,which has potential application for the diagnosis of *** the screened m Ab(C003)labeled with^(177)Lu was utilized for CA19–9 targeted RIT,which presents a significant suppression effect on the growth of colo205 xenografts than immunotherapy ***,the side effects of ^(177)Lu-DOTA-C003 are limited according to the results of in vivo ***89Zr-DFO-C003for CRC immune-PET imaging and ^(177)Lu-DOTA-C003 for RIT against CRC exhibit good potential in clinical applications.

关键词： Lutetium-177 CA19–9 Monoclonal antibody Colorectal cancer radioimmunotherapy

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