A Fully Human Insulin-Like Growth Factor-I Receptor Antibody SCH 717454 (Robatumumab) Has Antitumor Activity as a Single Agent and in Combination with Cytotoxics in Pediatric Tumor Xenografts

Abstract

The insulin-like growth factor-I receptor (IGF-IR) and its ligands (IGF-I and IGF-II) have been implicated in the growth, survival, and metastasis of a broad range of malignancies including pediatric tumors. Blocking the IGF-IR action is a potential cancer treatment. A fully human neutralizing monoclonal antibody, SCH 717454 (19D12, robatumumab), specific to IGF-IR, has shown potent antitumor effects in ovarian cancer in vitro and in vivo. In this study, SCH 717454 was evaluated in several pediatric solid tumors including neuroblastoma, osteosarcoma, and rhabdomyosarcoma. SCH 717454 is shown here to downregulate IGF-IR as well as inhibit IGF-IR and insulin receptor substrate-1 phosphorylation in pediatric tumor cells. IGF-IR and insulin receptor substrate-1 phosphorylation in the tumor cells. In vivo, SCH 717454 exhibits activity as a single agent and significantly inhibited growth of neuroblastoma, osteosarcoma, and rhabdomyosarcoma tumor xenografts. Combination of SCH 717454 with cisplatin or cyclophosphamide enhanced both the degree and the duration of the in vivo antitumor activity compared with single-agent treatments. Furthermore, SCH 717454 treatment markedly reduced Ki-67 expression and blood vessel formation in tumor xenografts, showing that the in vivo activity is derived from its inhibition of tumor cell proliferation and angiogenesis activity. Mol Cancer Ther; 9(2); 410-8. ©2010 AACR.

Obesity, type 2 diabetes, and cancer: the insulin and IGF connection

“…The overall result is inhibition of the IGF1R signaling cascade (Heidegger et al 2011). In vitro and in vivo studies with the monoclonal antibody robatumumab lead to inhibition of neuroblastoma, osteosarcoma, and rhabdomyosarcoma tumor cells and xenografts (Wang et al 2010). Studies using the IGF1R antibody AVE1642 demonstrate an inhibition of metastasis in metastatic breast cancer cell lines (Sachdev et al 2010).…”

Combination therapy approaches to target insulin-like growth factor receptor signaling in breast cancer

“…mAbs against IGF1R typically inhibit ligand-dependent receptor signaling by binding to the receptor competitively with its ligands IGF-1 and IGF-2 (Cohen et al 2005, Wang et al 2010a). An important component of their mode of action is also receptor downregulation (Burtrum et al 2003, Cohen et al 2005, Wang et al 2010a.…”

“…An important component of their mode of action is also receptor downregulation (Burtrum et al 2003, Cohen et al 2005, Wang et al 2010a. As a consequence of receptor blockade, circulating IGF-1 is markedly elevated (Yin et al 2013), although unable to elicit a receptor-mediated response.…”

The insulin-like growth factor (IGF) axis as an anticancer target in prostate cancer

“…IGF1R monoclonal antibodies are highly specific for IGF1R and do not bind INSR. Common mechanisms of action include inhibiting the receptor from ligand binding, triggering internalization or degradation of IGF1R or both [57,58]). In addition IGF1R monoclonal antibodies partially downregulate IGF1R/INSR hybrid receptors [57].…”