Eradication of Tumors through Simultaneous Ablation of CD276/B7-H3-Positive Tumor Cells and Tumor Vasculature

Seaman Steven; Zhu Zhongyu; Saha Saurabh; Zhang Xiaoyan M.; Yang Mi Young; Hilton Mary Beth; Morris Karen; Szot Christopher; Morris Holly; Swing Deborah A.; Tessarollo Lino; Smith Sean W.; Degrado Sylvia; Borkin Dmitry; Jain Nareshkumar; Scheiermann Julia; Feng Yang; Wang Yanping; Li Jinyu; Welsch Dean; DeCrescenzo Gary; Chaudhary Amit; Zudaire Enrique; Klarmann Kimberly D.; Keller Jonathan R.; Dimitrov Dimiter S.; Croix Brad St.

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Eradication of Tumors through Simultaneous Ablation of CD276/B7-H3-Positive Tumor Cells and Tumor Vasculature

机译：通过同时消除CD276 / B7-H3阳性肿瘤细胞和肿瘤脉管系统来消除肿瘤

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Targeting the tumor vasculature with antibody-drug conjugates (ADCs) is a promising anti-cancer strategy that in order to be realized must overcome several obstacles, including identification of suitable targets and optimal warheads. Here, we demonstrate that the cell-surface protein CD276/B7-H3 is broadly over-expressed by multiple tumor types on both cancer cells and tumor-infiltrating blood vessels, making it a potentially ideal dual-compartment therapeutic target. In preclinical studies CD276 ADCs armed with a conventional MMAE warhead destroyed CD276-positive cancer cells, but were ineffective against tumor vasculature. In contrast, pyrrolobenzodiazepine-conjugated CD276 ADCs killed both cancer cells and tumor vasculature, eradicating large established tumors and metastases, and improving long-term overall survival. CD276-targeted dual-compartment ablation could aid in the development of highly selective broad-acting anti-cancer therapies.

机译：针对抗体 - 药物缀合物（ADC）的靶向肿瘤脉管系统是一个有前途的抗癌策略，以便实现必须克服几个障碍，包括鉴定合适的目标和最佳弹头。这里，我们证明细胞表面蛋白CD276 / B7-H3在癌细胞和肿瘤浸润血管上广泛地过度表达，使其成为潜在理想的双隔室治疗靶标。在临床前研究CD276 ADCS携带常规MMAE弹头被破坏CD276阳性癌细胞，但对肿瘤脉管系统无效。相比之下，吡咯洛洛二氮杂己酮缀合的CD276 ADC杀死癌细胞和肿瘤脉管系统，消除了大规模的肿瘤和转移，并改善了长期整体存活。 CD276针对性的双隔室消融可以有助于开发高度选择性的广泛抗癌疗法。

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《Cancer Cell》 |2017年第4期|共23页
作者
Seaman Steven; Zhu Zhongyu; Saha Saurabh; Zhang Xiaoyan M.; Yang Mi Young; Hilton Mary Beth; Morris Karen; Szot Christopher; Morris Holly; Swing Deborah A.; Tessarollo Lino; Smith Sean W.; Degrado Sylvia; Borkin Dmitry; Jain Nareshkumar; Scheiermann Julia; Feng Yang; Wang Yanping; Li Jinyu; Welsch Dean; DeCrescenzo Gary; Chaudhary Amit; Zudaire Enrique; Klarmann Kimberly D.; Keller Jonathan R.; Dimitrov Dimiter S.; Croix Brad St.;
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作者单位

NCI Tumor Angiogenesis Unit MCGP NIH Frederick MD 21702 USA;

NCI Prot Interact Sect CIP NIH Frederick MD 21702 USA;

BioMed Valley Discoveries Inc Kansas City MO 64111 USA;

BioMed Valley Discoveries Inc Kansas City MO 64111 USA;

NCI Tumor Angiogenesis Unit MCGP NIH Frederick MD 21702 USA;

NCI Tumor Angiogenesis Unit MCGP NIH Frederick MD 21702 USA;

NCI Tumor Angiogenesis Unit MCGP NIH Frederick MD 21702 USA;

NCI Tumor Angiogenesis Unit MCGP NIH Frederick MD 21702 USA;

NCI Transgen Core Facil MCGP NIH Frederick MD 21702 USA;

NCI Neural Dev Sect MCGP NIH Frederick MD 21702 USA;

Abzena Bristol PA 19007 USA;

Abzena Bristol PA 19007 USA;

Abzena Bristol PA 19007 USA;

Abzena Bristol PA 19007 USA;

NCI CIP Immune Modulat Sect NIH Frederick MD 21702 USA;

NCI Prot Interact Sect CIP NIH Frederick MD 21702 USA;

NCI Prot Interact Sect CIP NIH Frederick MD 21702 USA;

NCI Prot Interact Sect CIP NIH Frederick MD 21702 USA;

BioMed Valley Discoveries Inc Kansas City MO 64111 USA;

BioMed Valley Discoveries Inc Kansas City MO 64111 USA;

NCI Tumor Angiogenesis Unit MCGP NIH Frederick MD 21702 USA;

NCI Tumor Angiogenesis Unit MCGP NIH Frederick MD 21702 USA;

NCI Basic Res Program Leidos Biomed Res Inc Frederick Natl Lab Canc Res Frederick MD 21702 USA;

NCI Basic Res Program Leidos Biomed Res Inc Frederick Natl Lab Canc Res Frederick MD 21702 USA;

NCI Prot Interact Sect CIP NIH Frederick MD 21702 USA;

NCI Tumor Angiogenesis Unit MCGP NIH Frederick MD 21702 USA;

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正文语种 eng
中图分类肿瘤学;
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1. Eradication of Tumors through Simultaneous Ablation of CD276/B7-H3-Positive Tumor Cells and Tumor Vasculature [J] . Seaman Steven, Zhu Zhongyu, Saha Saurabh, Cancer Cell . 2017,第4期

机译：通过同时消除CD276 / B7-H3阳性肿瘤细胞和肿瘤脉管系统来消除肿瘤
2. Enhancing Anti-PD-1/PD-L1 Immune Checkpoint Inhibitory Cancer Therapy by CD276-Targeted Photodynamic Ablation of Tumor Cells and Tumor Vasculature [J] . Bao Rui, Wang Yanpu, Lai Jianhao, Molecular pharmaceutics . 2019,第1期

机译：通过CD276靶向光动力消融肿瘤细胞和肿瘤脉管系统增强抗PD-1 / PD-L1免疫检查点抑制癌症治疗
3. Simultaneous targeting of tumor antigens and the tumor vasculature using t lymphocyte transfer synergize to induce regression of established tumors in mice [J] . ChinnasamyD., TranE., YuZ., Cancer research: The official organ of the American Association for Cancer Research, Inc . 2013,第11期

机译：使用t淋巴细胞转移同时靶向肿瘤抗原和肿瘤脉管系统可协同诱导小鼠已建立的肿瘤消退
4. Vasculature segmentation for radio frequency ablation of non- resectable hepatic tumors [C] . Paul F. Hemler, Evan S. McCreedy, Ruida Cheng, Image Processing pt.2; Progress in Biomedical Optics and Imaging; vol.7 no.30 . 2006

机译：不可分割的肝肿瘤射频消融的血管分割
5. Molecular studies on tumor cell-vasculature interactions: Adhesion molecules, endothelial cell retraction, tumor cell spreading, and modulatory role of eicosanoid 12(S)-HETE. [D] . Tang, Dean Guo. 1994

机译：肿瘤细胞与血管系统相互作用的分子研究：粘附分子，内皮细胞收缩，肿瘤细胞扩散和类花生酸12（S）-HETE的调节作用。
6. Eradication of Tumors through Simultaneous Ablation of CD276/B7-H3 Positive Tumor Cells and Tumor Vasculature [O] . Steven Seaman, Zhongyu Zhu, Saurabh Saha, -1

机译：通过同时消融CD276 / B7-H3阳性肿瘤细胞和肿瘤脉管系统根除肿瘤
7. Eradication of Tumors through Simultaneous Ablation of CD276/B7-H3-Positive Tumor Cells and Tumor Vasculature [O] . Steven Seaman, Zhongyu Zhu, Saurabh Saha, 2017

机译：通过同时消除CD276 / B7-H3阳性肿瘤细胞和肿瘤脉管系统来消除肿瘤
8. Enhanced Eradication of Lymphoma by Tumor-Specific Cytotoxic T-Cells Secreting an Engineered Tumor-Specific Immunotoxin [R] . Yotnda, P. 2010

机译：通过肿瘤特异性细胞毒性T细胞分泌工程化肿瘤特异性免疫毒素，增强根除淋巴瘤

Eradication of Tumors through Simultaneous Ablation of CD276/B7-H3-Positive Tumor Cells and Tumor Vasculature

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