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Radioimmunotherapy Targeting B7-H3 in situ glioma models enhanced antitumor efficacy by Reconstructing the tumor microenvironment.

ABSTRACT: Radionuclide drug conjugates (RDCs) with antibodies serve as a novel approach for the treatment of malignant tumors including glioblastoma. However, RDCs require optimal antibodies to work efficiently. Hu4G4, a novel B7-H3-targeting humanized monoclonal IgG1 antibody, is highly specific for the human B7-H3 protein (a marker of tumor cells, including glioblastoma cells). Herein, we established ¹³¹I-labeled hu4G4 (¹³¹I-hu4G4) and showed that it specifically bound to B7-H3 with high affinity (Kd = 0.99 ± 0.07 nM) and inhibited the growth of U87 cells in vitro. ¹³¹I-hu4G4 displayed potent in situ antitumor activity in a mouse model of glioma based on GL261 Red-Fluc-B7-H3 cells. More importantly, ¹³¹I-hu4G4 remodeled the tumor microenvironment and promoted the transformation of glioma from "cold" to "hot" tumors by promoting CD4⁺ and CD8⁺ T cell infiltration and the polarization of M2 to M1. Therefore, the antitumor activity observed with ¹³¹I-hu4G4, together with its ability to enhance antitumor immune responses, makes it a novel candidate for radioimmunotherapy of glioblastoma.

SUBMITTER: Zheng M

PROVIDER: S-EPMC10496502 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Radioimmunotherapy Targeting B7-H3 in situ glioma models enhanced antitumor efficacy by Reconstructing the tumor microenvironment.

Zheng Meng M Wang Yan Y Fu Fengqing F Zhang Kaijie K Wang Yanan Y Zhao Shandong S Liu Qingfeng Q Mu Huiwen H Zhang Xueguang X Miao Liyan L

International journal of biological sciences 20230815 13

Radionuclide drug conjugates (RDCs) with antibodies serve as a novel approach for the treatment of malignant tumors including glioblastoma. However, RDCs require optimal antibodies to work efficiently. Hu4G4, a novel B7-H3-targeting humanized monoclonal IgG1 antibody, is highly specific for the human B7-H3 protein (a marker of tumor cells, including glioblastoma cells). Herein, we established 131I-labeled hu4G4 (131I-hu4G4) and showed that it specifically bound to B7-H3 wit ...[more]

PMID: 37705739

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Project description:IntroductionNovel therapies that effectively kill both differentiated cancer cells and cancer initiating cells (CICs), which are implicated in causing chemotherapy-resistance and disease recurrence, are needed to reduce the morbidity and mortality of ovarian cancer. These studies used monoclonal antibody (mAb) 376.96, which recognizes a B7-H3 epitope expressed on ovarian cancer cells and CICs, as a carrier molecule for targeted α-particle radioimmunotherapy (RIT) in preclinical models of human ovarian cancer.MethodsmAb 376.96 was conjugated to the chelate 2-(4-isothiocyanotobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoylmethyl)-cyclododecane (TCMC) and radiolabeled with 212Pb, a source of α-particles. In vitro Scatchard assays determined the specific binding of 212Pb-376.96 to adherent differentiated or non-adherent CIC-enriched ES-2 and A2780cp20 ovarian cancer cells. Adherent ovarian cancer cells and non-adherent CIC-enriched tumorspheres treated in vitro with 212Pb-376.96 or the irrelevant isotype-matched 212Pb-F3-C25 were assessed for clonogenic survival. Mice bearing i.p. ES-2 or A2780cp20 xenografts were injected i.p. with 0.17-0.70MBq 212Pb-376.96 or 212Pb-F3-C25 and were used for in vivo imaging, ex vivo biodistribution, and therapeutic survival studies.Results212Pb-376.96 was obtained in high yield and purity (>98%); Kd values ranged from 10.6-26.6nM for ovarian cancer cells, with 104-105 binding sites/cell. 212Pb-376.96 inhibited the clonogenic survival of ovarian cancer cells up to 40 times more effectively than isotype-matched control 212Pb-F3-C25; combining 212Pb-376.96 with carboplatin significantly decreased clonogenic survival compared to either agent alone. In vivo imaging and biodistribution analysis 24h after i.p. injection of 212Pb-376.96 showed high peritoneal retention and tumor tissue accumulation (28.7% ID/g in ES-2 ascites, 73.1% ID/g in A2780cp20 tumors); normal tissues showed lower and comparable uptake for 212Pb-376.96 and 212Pb-F3-C25. Tumor-bearing mice treated with 212Pb-376.96 alone or combined with carboplatin survived 2-3 times longer than mice treated with 212Pb-F3-C25 or non-treated controls.ConclusionThese results support additional RIT studies with 212Pb-376.96 for future evaluation in patients with ovarian cancer.

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Radioimmunotherapy Targeting B7-H3 in situ glioma models enhanced antitumor efficacy by Reconstructing the tumor microenvironment.

Publications

Radioimmunotherapy Targeting B7-H3 <i>in situ</i> glioma models enhanced antitumor efficacy by Reconstructing the tumor microenvironment.

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