Therapeutic Targeting of the IGF Axis
Abstract
:1. Introduction
2. Disease States Characterized by IGF Axis Activation
2.1. Cancer
2.2. Endocrine Disorders
2.2.1. Acromegaly
2.2.2. Diabetes
2.2.3. Thyroid Eye Disease
2.3. Skin Diseases
2.3.1. Psoriasis
2.3.2. Acne
2.4. Frailty and Lifespan
3. Therapeutic Strategies for Targeting IGF-1R in Cancer
3.1. Molecular Approaches
3.1.1. Antisense Oligonucleotides
3.1.2. siRNAs
3.1.3. Dominant Negative Receptors
3.2. Anti-IGF-1R Agents
3.2.1. IGF-1R Antibodies
3.2.2. Tyrosine Kinase Inhibitors (TKIs)
3.3. Targeting IGF Ligands
3.3.1. IGF Neutralizating Antibodies
3.3.2. IGF Ligand-TRAPs
3.3.3. Recombinant IGFBPs
3.3.4. PAPP-A Inhibition
3.4. Natural Products That Inhibit the IGF Axis
4. Therapeutic Use of IGF Axis Inhibitors: Current Status
4.1. Negative Trials of IGF-1R mABs and TKIs in Cancer Patients
4.2. Potential Grounds for Cautious Optimism
4.3. Repurposing IGF Axis Inhibitors for Non-Malignant Disorders
5. Conclusions
Funding
Acknowledgments
Conflicts of Interest
References
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Antibody | Humanized | Class | Potency (IC50) IGF-1R | Potency (IC50) INSR | Clinical Trial Phase | References |
---|---|---|---|---|---|---|
Figitumumab (CP-751,871) | Fully human | IgG2a | 1.8 nM | N/A | III | [152,153,154,155,156] |
Ganitumab (AMG 479) | Fully human | IgG1 | 2 nM | >50 nM | III | [157,158,159] |
Teprotumumab (R1507) | Fully human | IgG1 | 0.5 nM | N/A | II | [160,161,162,163] |
Dalotuzumab (MK-0646) | Humanized | IgG1 | 1 nM | N/A | III | [164,165,166,167] |
Cixutumumab (IMC-A12) | Fully human | IgG1 | 0.6–1 nM | N/A | II | [168,169,170,171] |
Robatumumab (SCH 717454) | Fully human | IgG1 | 2.7 nM | N/A | II | [172,173] |
Istiratumab (MM-141) | Engineered human | IgG1 with 2 scFvs | 2 nM | Bispecific IGF-1R/ErbB3 | II | [174] |
BIIB022 | Fully human | IgG4 | <10 nM | N/A | I | [175,176] |
Drug Name | Mode of Inhibition | Potency (IC50) IGF-1R INSR | Additional Targets | Clinical Trial Phase | References | |
---|---|---|---|---|---|---|
Linsitinib (OSI-906) | ATP competitive | 35 nM | 75 nM | N/A | III | [145,181,184,185,186,187,192,193] |
BMS-754807 | ATP competitive, | 1.8 nM | 1.7 nM | MET, RON, TrkA/B, AurA/B | II | [182,194] |
XL-228 | ATP competitive | 1.6 nM | N/A | BCR-ABL, AurA, SRC, LYN | I | [189,195] |
AXL1717 (Picropodophyllin) | Non-ATP competitive | 40 nM | N/A | Microtubules | II | [190,191,196,197] |
Masoprocol (INSM-18, nordihydroguaiaretic acid) | Non-ATP competitive natural product of Larrea divaricata | 31 µM | N/A | HER2 | II | [188,198,199] |
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Osher, E.; Macaulay, V.M. Therapeutic Targeting of the IGF Axis. Cells 2019, 8, 895. https://doi.org/10.3390/cells8080895
Osher E, Macaulay VM. Therapeutic Targeting of the IGF Axis. Cells. 2019; 8(8):895. https://doi.org/10.3390/cells8080895
Chicago/Turabian StyleOsher, Eliot, and Valentine M. Macaulay. 2019. "Therapeutic Targeting of the IGF Axis" Cells 8, no. 8: 895. https://doi.org/10.3390/cells8080895