@article{208f1cbfc1ba4f709ff247f9aca8235f,
title = "Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy",
abstract = "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. Zheng et al. develop 15D11, a fully human monoclonal antibody to Jagged1, which inhibits Jagged1 on breast cancer cells as well as blocking metastasis-promoting effects of osteoblast-derived Jagged1 induced by chemotherapy. 15D11 reduces bone metastasis and sensitizes metastases to chemotherapy in mouse models of breast cancer.",
keywords = "Jagged1, bone metastasis, breast cancer, chemoresistance, neutralizing antibody, osteoblastic niche, osteoblasts",
author = "Hanqiu Zheng and Yangjin Bae and Sabine Kasimir-Bauer and Rebecca Tang and Jin Chen and Guangwen Ren and Min Yuan and Mark Esposito and Wenyang Li and Yong Wei and Minhong Shen and Lanjing Zhang and Nikolai Tupitsyn and Klaus Pantel and Chadwick King and Jan Sun and Jodi Moriguchi and Jun, {Helen Toni} and Angela Coxon and Brendan Lee and Yibin Kang",
note = "Funding Information: We thank N. Sethi, B. Ell, R. Chakrabarti, T. Celia-Terrassa, L. Wan, H.A. Smith, Z. Li, W. Lu, and other lab members for technical support and helpful discussions, and J.J. Grady and C. DeCoste for assistance with flow cytometry, and T. Campbell at Rutgers Cancer Institute of New Jersey (RCINJ) Preclinical Imaging Facility for μCT imaging. We thank M. Alpern and V. Buynevich of the University Medical Center of Princeton at Plainsboro for assistance in blood sample analysis. We thank those key scientists, particularly L. Perkins and J. Ho, at Amgen Discovery Research who contributed to the development of the 15D11 antibody. This research was supported by an RCINJ Research Development Award, the Brewster Foundation , and grants from METAvivor Research and Support ( AWD1004691 ), the U.S. Department of Defense ( BC123187 ), the NIH ( R01CA134519 and R01CA141062 ), and Amgen to Y.K., Cancer Prevention and Research Institute of Texas (CPRIT) grant RP170488 to B.L. and Y.B., and postdoctoral fellowships from Susan G. Komen to H.Z. ( KG111164 ) and M.S. ( PDF17332118 ), from DOD to G.R. ( BC123284 ), and from NJCCR to M.S. ( DFHS15PPCO21 ). This research was also supported by the Preclinical Imaging Facility and Pre-clinical Imaging and Flow Cytometry Shared Resources of the RCINJ ( P30CA072720 ). C.K., J.S., J.M., H.T.J., and A.C. are either previous or current employees of Amgen. This research was supported in part by a grant from Amgen. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = dec,
day = "11",
doi = "10.1016/j.ccell.2017.11.002",
language = "English (US)",
volume = "32",
pages = "731--747.e6",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "6",
}