Abstract
The insulin-like growth factor (IGF)-axis was implicated in cancer progression and identified as a clinically important therapeutic target. Several IGF-I receptor (IGF-IR) targeting drugs including humanized monoclonal antibodies have advanced to phase II/III clinical trials, but to date, have not progressed to clinical use, due, at least in part, to interference with insulin receptor signaling and compensatory signaling by the insulin receptor (IR) isoform A that can bind IGF-II and initiate mitogenic signaling. Here we briefly review the current state of IGF-targeting biologicals, discuss some factors that may be responsible for their poor performance in the clinic and outline the stepwise bioengineering and validation of an IGF-Trap—a novel anti-cancer therapeutic that could bypass these limitations. The IGF-Trap is a heterotetramer, consisting of the entire extracellular domain of the IGF-IR fused to the Fc portion of human IgG1. It binds human IGF-I and IGF-II with a three-log higher affinity than insulin and could inhibit IGF-IR driven cellular functions such as survival, proliferation and invasion in multiple carcinoma cell models in vitro. In vivo, the IGF-Trap has favorable pharmacokinetic properties and could markedly reduce metastatic outgrowth of colon and lung carcinoma cells in the liver, outperforming IGF-IR and ligand-binding monoclonal antibodies. Moreover, IGF-Trap dose-response profiles correlate with their bio-availability profiles, as measured by the IGF kinase receptor-activation (KIRA) assay, providing a novel, surrogate biomarker for drug efficacy. Our studies identify the IGF-Trap as a potent, safe, anti-cancer therapeutic that could overcome some of the obstacles encountered by IGF-targeting biologicals that have already been evaluated in clinical settings.
Highlights
The tyrosine kinase domain in the β subunit is activated, inducing a conformational change that leads to autophosphorylation at Tyr950 that serves as a docking site for signalling substrates including the insulin receptor substrate (IRS) proteins IRS-1-4, and the activation of PI3-kinase (PI3K)/Akt/ mammalian target of rapamycin and Raf /MEK/ERK signaling
Increased expression of insulin-like growth factor (IGF)-IR and/or its ligands has been documented in many human malignancies such as lung, breast, colon and prostate carcinoma, glioblastoma and melanoma, and high expression levels were shown to be associated with metastasis, shorter survival and poor prognosis [19], identifying this axis as a target for cancer therapy
The results showed that sustained delivery of a soluble IGF-I receptor (IGF-IR) decoy was highly effective in preventing the expansion of liver metastases
Summary
The IGF-axis consists of two cell surface receptors (IGF-IR and IGF-IIR), the ligands IGF-I and IGF-II, high affinity binding proteins (IGFBP-1-6) and their proteases The tyrosine kinase domain in the β subunit is activated, inducing a conformational change that leads to autophosphorylation at Tyr950 that serves as a docking site for signalling substrates including the insulin receptor substrate (IRS) proteins IRS-1-4, and the activation of PI3-kinase (PI3K)/Akt/ mammalian target of rapamycin (mTOR) and Raf /MEK/ERK signaling. This leads to regulation of cell survival and protein synthesis on one hand, and gene expression, cellular proliferation and differentiation, on the other [4,5]. Codony-Servat el al. showed that in colorectal carcinoma cells treated with IGF-IR-blocking antibodies, nuclear translocation increased, suggesting that nuclear sequestration of the receptor could contribute to therapy resistance [9]
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