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

Cancer Cell. 2017 Dec 11;32(6):731-747.e6. doi: 10.1016/j.ccell.2017.11.002.

Authors

Hanqiu Zheng¹, Yangjin Bae², Sabine Kasimir-Bauer³, Rebecca Tang¹, Jin Chen¹, Guangwen Ren¹, Min Yuan¹, Mark Esposito¹, Wenyang Li¹, Yong Wei¹, Minhong Shen¹, Lanjing Zhang⁴, Nikolai Tupitsyn⁵, Klaus Pantel⁶, Chadwick King⁷, Jan Sun⁷, Jodi Moriguchi⁷, Helen Toni Jun⁸, Angela Coxon⁷, Brendan Lee⁹, Yibin Kang¹⁰

Affiliations

¹ Department of Molecular Biology, Princeton University, Washington Road, LTL 255, Princeton, NJ 08544, USA.
² Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Room R814 BCM225, Houston, TX 77030, USA.
³ Department of Gynecology and Obstetrics, University Hospital Essen, Essen, Germany.
⁴ Department of Pathology, University Medical Center of Princeton, Plainsboro, NJ, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
⁵ Laboratory of Hematopoiesis Immunology, Cancer Research Center, Moscow, Russia.
⁶ Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Center of Experimental Medicine, Hamburg, Germany.
⁷ Oncology Research, Amgen Inc., Thousand Oaks, CA 91320, USA.
⁸ MabVax Therapeutics Holdings, Inc., San Diego, CA 92121, USA.
⁹ Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Room R814 BCM225, Houston, TX 77030, USA. Electronic address: blee@bcm.edu.
¹⁰ 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. Electronic address: ykang@princeton.edu.

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.

Keywords: Jagged1; bone metastasis; breast cancer; chemoresistance; neutralizing antibody; osteoblastic niche; osteoblasts.

MeSH terms

Animals
Antibodies, Monoclonal / pharmacology*
Antineoplastic Agents / pharmacology*
Bone Neoplasms / drug therapy*
Bone Neoplasms / secondary*
Humans
Jagged-1 Protein / antagonists & inhibitors*
Mice
Mice, Transgenic
Osteoblasts / drug effects
Xenograft Model Antitumor Assays

Substances

Antibodies, Monoclonal
Antineoplastic Agents
Jagged-1 Protein

Abstract

MeSH terms

Substances

Grants and funding