A dual-specific anti-IGF-1/IGF-2 human monoclonal antibody alone and in combination with temsirolimus for therapy of neuroblastoma.
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.
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY.|Laboratory of Fully Human Antibody Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Guangdong, China.
Qi
Q
Zhao
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY.
Hoa
H
Tran
Protein 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.
Dimiter S
DS
Dimitrov
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY.
Nai-Kong V
NK
Cheung
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000737:chemistry; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D016466:CHO Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004357:Drug Synergism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000276:immunology; D007335:Insulin-Like Growth Factor II / Q000037:antagonists & inhibitors / Q000276:immunology; D016513:Mice, SCID; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D011485:Protein Binding; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C000602350:m708.5 monoclonal antibody; C401859:temsirolimus; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D020123:Sirolimus
IGF-1; IGF-2; chemotherapy; neuroblastoma; temsirolimus