Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy.,Cancer Cell

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Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy.
Cancer Cell ( IF 48.8 ) Pub Date : 2017-Dec-11 , DOI: 10.1016/j.ccell.2017.11.002
Hanqiu Zheng ₁ , Yangjin Bae ₂ , Sabine Kasimir-Bauer ₃ , Rebecca Tang ₁ , Jin Chen ₁ , Guangwen Ren ₁ , Min Yuan ₁ , Mark Esposito ₁ , Wenyang Li ₁ , Yong Wei ₁ , Minhong Shen ₁ , Lanjing Zhang ₄ , Nikolai Tupitsyn ₅ , Klaus Pantel ₆ , Chadwick King ₇ , Jan Sun ₇ , Jodi Moriguchi ₇ , Helen Toni Jun ₈ , Angela Coxon ₇ , Brendan Lee ₂ , Yibin Kang ₉

Affiliation

Department of Molecular Biology, Princeton University, Washington Road, LTL 255, Princeton, NJ 08544, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Room R814 BCM225, Houston, TX 77030, USA.
Department of Gynecology and Obstetrics, University Hospital Essen, Essen, Germany.
Department of Pathology, University Medical Center of Princeton, Plainsboro, NJ, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
Laboratory of Hematopoiesis Immunology, Cancer Research Center, Moscow, Russia.
Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Center of Experimental Medicine, Hamburg, Germany.
Oncology Research, Amgen Inc., Thousand Oaks, CA 91320, USA.
MabVax Therapeutics Holdings, Inc., San Diego, CA 92121, USA.
Department of Molecular Biology, Princeton University, Washington Road, LTL 255, Princeton, NJ 08544, USA; Cancer Metabolism and Growth Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.

Bone metastasis is a major health threat to breast cancer patients. Tumor-derived Jagged1 represents a central node in mediating tumor-stromal interactions that promote osteolytic bone metastasis. Here, we report the development of a highly effective fully human monoclonal antibody against Jagged1 (clone 15D11). In addition to its inhibitory effect on bone metastasis of Jagged1-expressing tumor cells, 15D11 dramatically sensitizes bone metastasis to chemotherapy, which induces Jagged1 expression in osteoblasts to provide a survival niche for cancer cells. We further confirm the bone metastasis-promoting function of osteoblast-derived Jagged1 using osteoblast-specific Jagged1 transgenic mouse model. These findings establish 15D11 as a potential therapeutic agent for the prevention or treatment of bone metastasis.

中文翻译：

靶向肿瘤和成骨细胞微环境衍生的 Jagged1 的治疗性抗体使骨转移对化疗敏感。

骨转移是乳腺癌患者的主要健康威胁。肿瘤源性 Jagged1 代表介导肿瘤-基质相互作用的中心节点，促进溶骨性骨转移。在此，我们报告了针对 Jagged1（克隆 15D11）的高效全人单克隆抗体的开发。除了对表达 Jagged1 的肿瘤细胞骨转移有抑制作用外，15D11 还能显着提高骨转移对化疗的敏感性，从而诱导成骨细胞中 Jagged1 的表达，为癌细胞提供生存环境。我们使用成骨细胞特异性 Jagged1 转基因小鼠模型进一步证实了成骨细胞衍生的 Jagged1 的骨转移促进功能。这些发现确立了 15D11 作为预防或治疗骨转移的潜在治疗剂。

更新日期：2017-12-11

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