A dual-specific anti-IGF-1/IGF-2 human monoclonal antibody alone and in combination with temsirolimus for therapy of neuroblastoma Journal Article
| Authors: | Zhao, Q.; Tran, H.; Dimitrov, D. S.; Cheung, N. K. V. |
| Article Title: | A dual-specific anti-IGF-1/IGF-2 human monoclonal antibody alone and in combination with temsirolimus for therapy of neuroblastoma |
| Abstract: | 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. What's new? Insulin-like growth factors (IGF) 1 and 2 promote the biogenesis of neuroblastoma, a frequent neuroendocrine tumor in early childhood. Here the authors show that targeting IGF-1 and 2 with a specific antibody (m708.5) has anti-tumor activity in neuroblastoma cell lines as well as in cell culture models of the Ewing family of tumors, rhabdomyosarcoma, and osteosarcoma. Similarly, in xenograft mouse models of neuroblastoma, m798.5 together with an inhibitor of mammalian target of rapamycin (mTOR) suppressed tumor growth and increased survival, supporting a potential clinical application of antibodies targeting IGF-1/2 in children afflicted with solid tumors. © 2015 UICC. |
| Keywords: | osteosarcoma; cancer survival; controlled study; protein phosphorylation; unclassified drug; human cell; cisplatin; doxorubicin; drug potentiation; nonhuman; chemotherapy; binding affinity; mouse; animal experiment; animal model; vincristine; antineoplastic activity; in vitro study; monoclonal antibody; somatomedin c receptor; temsirolimus; ewing sarcoma; cancer inhibition; neuroblastoma; somatomedin c; rhabdomyosarcoma; receptor binding; somatomedin b; somatomedin b receptor; igf-1; human; priority journal; article; igf-2; firtecan; monoclonal antibody m708.5 |
| Journal Title: | International Journal of Cancer |
| Volume: | 137 |
| Issue: | 9 |
| ISSN: | 0020-7136 |
| Publisher: | John Wiley & Sons |
| Date Published: | 2015-11-01 |
| Start Page: | 2243 |
| End Page: | 2252 |
| Language: | English |
| DOI: | 10.1002/ijc.29588 |
| PROVIDER: | scopus |
| PUBMED: | 25924852 |
| PMCID: | PMC4978514 |
| DOI/URL: | |
| Notes: | Export Date: 2 September 2015 -- Source: Scopus |
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