Abstract
The insulin-like growth factor (IGF) axis has been implicated in the progression of malignant disease and identified as a clinically important therapeutic target. Several IGF-1 receptor (IGF-1R) 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 signalling. We previously reported on the production of a soluble fusion protein consisting of the extracellular domain of human IGF-1R fused to the Fc portion of human IgG1 (first generation IGF-TRAP) that bound human IGF-1 and IGF-2 with a 3 log higher affinity than insulin. We showed that the IGF-TRAP had potent anti-cancer activity in several pre-clinical models of aggressive carcinomas. Here we report on the re-engineering of the IGF-TRAP with the aim of improving physicochemical properties and suitability for clinical applications. We show that cysteine-serine substitutions in the Fc hinge region of IGF-TRAP eliminated high-molecular-weight oligomerized species, while a further addition of a flexible linker, not only improved the pharmacokinetic profile, but also enhanced the therapeutic profile of the IGF-TRAP, as evaluated in an experimental colon carcinoma metastasis model. Dose-response profiles of the modified IGF-TRAPs correlated with their bio-availability profiles, as measured by the IGF kinase-receptor-activation (KIRA) assay, providing a novel, surrogate biomarker for drug efficacy. This study provides a compelling example of structure-based re-engineering of Fc-fusion-based biologics for better manufacturability that also significantly improved pharmacological parameters. It identifies the re-engineered IGF-TRAP as a potent anti-cancer therapeutic.
Highlights
The insulin-like growth factor (IGF) axis consisting of the heterotetrameric IGF-1 receptor (IGF-1R) and its high affinity binding ligands IGF-1 and IGF-2 have been implicated in all stages of cancer growth and progression including cellular transformation, epithelial-to-mesenchymal transition (EMT), invasion and metastasis, as well as in the regulation of the tumor microenvironment[1,2,3,4,5]
We previously reported on the production of a soluble fusion protein consisting of the extracellular domain of human IGF-1R fused to the Fc portion of human IgG115
We showed that the IGF-TRAP bound human IGF-1 and IGF-2 with high affinities and human insulin with a 1000-fold lower affinity, mimicking the KD values reported for the native receptor
Summary
The insulin-like growth factor (IGF) axis consisting of the heterotetrameric IGF-1 receptor (IGF-1R) and its high affinity binding ligands IGF-1 and IGF-2 have been implicated in all stages of cancer growth and progression including cellular transformation, epithelial-to-mesenchymal transition (EMT), invasion and metastasis, as well as in the regulation of the tumor microenvironment[1,2,3,4,5]. In addition to lack of efficacy, the high homology between IR and IGF-1R has resulted in undesirable side effects, including hyperinsulinemia and hyperglycemia following treatment with some of these inhibitors These obstacles to therapeutic efficacy have led to development of a new therapeutic strategy with a class of drugs that target the ligands instead of the receptor. MAb BI 836845 (Xentuzumab) developed by Boehringer Ingelheim, has advanced to a phase I clinical trial (ClinicalTrials.gov; NCT01403974) and is in phase Ib, in combination with a CDK4/6 inhibitor for HR+/HER2− metastatic breast cancer and other solid tumors[11] Another effective strategy for blocking the action of cell surface receptors is the use of soluble receptor decoys that bind the ligands with high affinity, reducing their bioavailability to the cognate receptor in a highly specific manner[12,13,14]. A soluble TNF-α receptor-Fc fusion protein (TNF-TRAP, Etanercept or Enbrel) is currently in routine clinical use for the treatment of inflammatory conditions such as rheumatoid arthritis[13] and a VEGFR1/VEGFR2-Fc decoy (VEGF-TRAP, Aflibercept) is approved for the treatment of wet macular degeneration under the trade name Eylea, and for metastatic colorectal cancer as Zal-TRAP12
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