Targeting the IGF-Axis for Cancer Therapy: Development and Validation of an IGF-Trap as a Potential Drug
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 p...
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doaj-4b4690c9c9b94c0d8017cd8ccb9e18542020-11-25T02:37:49ZengMDPI AGCells2073-44092020-04-0191098109810.3390/cells9051098Targeting the IGF-Axis for Cancer Therapy: Development and Validation of an IGF-Trap as a Potential DrugYinhsuan Michely Chen0Shu Qi1Stephanie Perrino2Masakazu Hashimoto3Pnina Brodt4Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, CanadaThe Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, CanadaThe Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, CanadaThe Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, CanadaDepartment of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, CanadaThe 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 IgG<sub>1</sub>. 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.https://www.mdpi.com/2073-4409/9/5/1098IGF-I receptorsignalingtargeted therapeuticsIGF-Trap |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yinhsuan Michely Chen Shu Qi Stephanie Perrino Masakazu Hashimoto Pnina Brodt |
spellingShingle |
Yinhsuan Michely Chen Shu Qi Stephanie Perrino Masakazu Hashimoto Pnina Brodt Targeting the IGF-Axis for Cancer Therapy: Development and Validation of an IGF-Trap as a Potential Drug Cells IGF-I receptor signaling targeted therapeutics IGF-Trap |
author_facet |
Yinhsuan Michely Chen Shu Qi Stephanie Perrino Masakazu Hashimoto Pnina Brodt |
author_sort |
Yinhsuan Michely Chen |
title |
Targeting the IGF-Axis for Cancer Therapy: Development and Validation of an IGF-Trap as a Potential Drug |
title_short |
Targeting the IGF-Axis for Cancer Therapy: Development and Validation of an IGF-Trap as a Potential Drug |
title_full |
Targeting the IGF-Axis for Cancer Therapy: Development and Validation of an IGF-Trap as a Potential Drug |
title_fullStr |
Targeting the IGF-Axis for Cancer Therapy: Development and Validation of an IGF-Trap as a Potential Drug |
title_full_unstemmed |
Targeting the IGF-Axis for Cancer Therapy: Development and Validation of an IGF-Trap as a Potential Drug |
title_sort |
targeting the igf-axis for cancer therapy: development and validation of an igf-trap as a potential drug |
publisher |
MDPI AG |
series |
Cells |
issn |
2073-4409 |
publishDate |
2020-04-01 |
description |
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 IgG<sub>1</sub>. 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. |
topic |
IGF-I receptor signaling targeted therapeutics IGF-Trap |
url |
https://www.mdpi.com/2073-4409/9/5/1098 |
work_keys_str_mv |
AT yinhsuanmichelychen targetingtheigfaxisforcancertherapydevelopmentandvalidationofanigftrapasapotentialdrug AT shuqi targetingtheigfaxisforcancertherapydevelopmentandvalidationofanigftrapasapotentialdrug AT stephanieperrino targetingtheigfaxisforcancertherapydevelopmentandvalidationofanigftrapasapotentialdrug AT masakazuhashimoto targetingtheigfaxisforcancertherapydevelopmentandvalidationofanigftrapasapotentialdrug AT pninabrodt targetingtheigfaxisforcancertherapydevelopmentandvalidationofanigftrapasapotentialdrug |
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1724793245021503488 |