A dual‐specific anti‐IGF‐1/IGF‐2 human monoclonal antibody alone and in combination with temsirolimus for therapy of neuroblastoma

International Journal of Cancer - Tập 137 Số 9 - Trang 2243-2252 - 2015
Qi Zhao1,2, Hoa Tran1, Dimiter S. Dimitrov3, Nai‐Kong V. Cheung1
1Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY
2Laboratory of Fully Human Antibody Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Guangdong, China
3Protein Interaction Section, Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD, USA

Tóm tắt

The insulin‐like growth factors (IGFs), IGF‐1 and IGF‐2, have been implicated in the growth, survival and metastasis of a broad range of malignancies including pediatric tumors. They bind to the IGF receptor type 1 (IGF‐1R) and the insulin receptor (IR) which are overexpressed in many types of solid malignancies. Activation of the IR by IGF‐2 results in increased survival of tumor cells. We have previously identified a novel human monoclonal antibody, m708.5, which binds with high (pM) affinity to both human IGF‐1 and IGF‐2, and potently inhibits phosphorylation of the IGF‐1R and the IR in tumor cells. m708.5 exhibited strong antitumor activity as a single agent against most cell lines derived from neuroblastoma, Ewing family of tumor, rhabdomyosarcoma and osteosarcoma. When tested in neuroblastoma cell lines, it showed strong synergy with temsirolimus and synergy with chemotherapeutic agents in vitro. In xenograft models, the combination of m708.5 and temsirolimus significantly inhibited neuroblastoma growth and prolonged mouse survival. Taken together, these results support the clinical development of m708.5 for pediatric solid tumors with potential for synergy with chemotherapy and mTOR inhibitors.

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International Journal of Cancer

Tập 137 Số 9

2243-2252

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