Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy

Hanqiu Zheng; Yangjin Bae; Sabine Kasimir-Bauer; Rebecca Tang; Jin Chen; Guangwen Ren; Min Yuan; Mark Esposito; Wenyang Li; Yong Wei; Minhong Shen; Lanjing Zhang; Nikolai Tupitsyn; Klaus Pantel; Chadwick King; Jan Sun; Jodi Moriguchi; Helen Toni Jun; Angela Coxon; Brendan Lee; Yibin Kang

doi:10.1016/j.ccell.2017.11.002

Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy

Hanqiu Zheng, Yangjin Bae, Sabine Kasimir-Bauer, Rebecca Tang, Jin Chen, Guangwen Ren, Min Yuan, Mark Esposito, Wenyang Li, Yong Wei, Minhong Shen, Lanjing Zhang, Nikolai Tupitsyn, Klaus Pantel, Chadwick King, Jan Sun, Jodi Moriguchi, Helen Toni Jun, Angela Coxon, Brendan LeeYibin Kang

Research output: Contribution to journal › Article › peer-review

133 Scopus citations

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.

Original language	English (US)
Pages (from-to)	731-747.e6
Journal	Cancer Cell
Volume	32
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2017.11.002
State	Published - Dec 11 2017

All Science Journal Classification (ASJC) codes

Oncology
Cancer Research

Keywords

Jagged1
bone metastasis
breast cancer
chemoresistance
neutralizing antibody
osteoblastic niche
osteoblasts

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10.1016/j.ccell.2017.11.002

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Zheng, H., Bae, Y., Kasimir-Bauer, S., Tang, R., Chen, J., Ren, G., Yuan, M., Esposito, M., Li, W., Wei, Y., Shen, M., Zhang, L., Tupitsyn, N., Pantel, K., King, C., Sun, J., Moriguchi, J., Jun, H. T., Coxon, A., ... Kang, Y. (2017). Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy. Cancer Cell, 32(6), 731-747.e6. https://doi.org/10.1016/j.ccell.2017.11.002

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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",

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Zheng, H, Bae, Y, Kasimir-Bauer, S, Tang, R, Chen, J, Ren, G, Yuan, M, Esposito, M, Li, W, Wei, Y, Shen, M, Zhang, L, Tupitsyn, N, Pantel, K, King, C, Sun, J, Moriguchi, J, Jun, HT, Coxon, A, Lee, B & Kang, Y 2017, 'Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy', Cancer Cell, vol. 32, no. 6, pp. 731-747.e6. https://doi.org/10.1016/j.ccell.2017.11.002

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T1 - Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy

AU - Zheng, Hanqiu

AU - Bae, Yangjin

AU - Kasimir-Bauer, Sabine

AU - Tang, Rebecca

AU - Chen, Jin

AU - Ren, Guangwen

AU - Yuan, Min

AU - Esposito, Mark

AU - Li, Wenyang

AU - Wei, Yong

AU - Shen, Minhong

AU - Zhang, Lanjing

AU - Tupitsyn, Nikolai

AU - Pantel, Klaus

AU - King, Chadwick

AU - Sun, Jan

AU - Moriguchi, Jodi

AU - Jun, Helen Toni

AU - Coxon, Angela

AU - Lee, Brendan

AU - Kang, Yibin

PY - 2017/12/11

Y1 - 2017/12/11

N2 - 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.

AB - 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.

KW - Jagged1

KW - bone metastasis

KW - breast cancer

KW - chemoresistance

KW - neutralizing antibody

KW - osteoblastic niche

KW - osteoblasts

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SN - 1535-6108

VL - 32

SP - 731-747.e6

JO - Cancer Cell

JF - Cancer Cell

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Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy

Abstract

All Science Journal Classification (ASJC) codes

Keywords

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