Dalotuzumab

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Dalotuzumab
Monoclonal antibody
Type Whole antibody
Source Humanized (from mouse)
Target IGF-1 receptor
Clinical data
ATC code
  • none
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG
ECHA InfoCard 100.205.569 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C6528H10086N1730O2018S40
Molar mass 146374.99 g·mol−1
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Dalotuzumab is an anti-IGF1 receptor (IGF1R) humanized monoclonal antibody designed for the potential treatment of various cancers. [1] Common adverse effects include hyperglycemia, nausea, vomiting, and fatigue. [2] Dalotuzumab was developed by Merck and Co., Inc. [3]

Contents

Indications

Dalotuzumab is indicated to treat breast cancer, colorectal cancer, multiple myeloma, neuroendocrine tumors, non-small cell lung cancer (NSCLC), pancreatic cancer, and solid tumors. [1]

Adverse effects

Adverse effects of Dalotuzumab: [1] [2] [4]

Mechanism of action

Insulin-like growth factors (IGFs) are pivotal in cellular processes contributing to normal physiology as well as certain pathologies (e.g., cancer). [3] The IGF family of proteins, also known as the IGF axis, consists of three ligands (insulin, IGF1, IGF2), three cell surface receptors (insulin receptor [IR], IGF1 receptor [IGF1R], IGF2 receptor [IGF2R]), and seven IGF binding proteins (IGFBP1-7). [5] Notably, IGF1R serves as the primary receptor within the IGF axis. [5] The IGF1R is a receptor tyrosine kinase (RTK) with a heterotetrameric structure composed of two extracellular α subunits and two transmembrane β subunits. [3] [5] Upon ligand-induced activation of this receptor, cytoplasmic adaptor proteins, Src-homology collagen (Shc) and insulin receptor substrate (IRS), are phosphorylated and, in turn, trigger the activation of the Ras/Raf/MEK/Erk and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways, respectively. [3] These signaling pathways are involved in the regulation of cell survival and cell cycle progression. [3]

Furthermore, IGF1R amplification and overexpression have been observed in the formation of tumors and metastasis of various human cancers. [5] These findings justified the development of anti-IGF1R therapies with the goal of inhibiting aberrant receptor activity and potentially yielding anticancer effects. [3] Among said therapies, Dalotuzumab, a humanized monoclonal antibody, was designed to target and bind the extracellular domains of IGF1R, effectively blocking ligand activation of the receptor and preventing downstream signaling. [3] Moreover, the binding of Dalotuzumab to IGF1R, as seen with other anti-IGF1R antibodies, downregulates the expression of the receptors by prompting the internalization and degradation of IGF1R. [3]

Figure 1: Mechanism of Action of Dalotuzumab Mechanism of Action of Dalotuzumab.jpg
Figure 1: Mechanism of Action of Dalotuzumab

History

There are more than 30 different anti-IGF1R candidate drugs involved in over 70 industry and academic-initiated clinical trials. [6]

Dalotuzumab (MK-0646) was developed by Merck and Co., Inc. under license from French pharmaceutical company, Pierre Fabre. [3] Dalotuzumab presently remains in clinical trials and has not been granted FDA approval. [7]

References

  1. 1 2 3 Scartozzi M, Bianconi M, Maccaroni E, Giampieri R, Berardi R, Cascinu S (June 2010). "Dalotuzumab, a recombinant humanized mAb targeted against IGFR1 for the treatment of cancer". Current Opinion in Molecular Therapeutics. 12 (3): 361–371. PMID   20521225.
  2. 1 2 Ma H, Zhang T, Shen H, Cao H, Du J (June 2014). "The adverse events profile of anti-IGF-1R monoclonal antibodies in cancer therapy". British Journal of Clinical Pharmacology. 77 (6): 917–928. doi:10.1111/bcp.12228. PMC   4093917 . PMID   24033707.
  3. 1 2 3 4 5 6 7 8 9 "Dalotuzumab Overview". Creative Biolabs. Retrieved 2023-01-01.
  4. ↑ Gupta S, Engstrom PF, Cohen SJ (December 2011). "Emerging therapies for advanced gastroenteropancreatic neuroendocrine tumors". Clinical Colorectal Cancer. 10 (4): 298–309. doi:10.1016/j.clcc.2011.06.006. PMID   21813338.
  5. 1 2 3 4 Wang P, Mak VC, Cheung LW (January 2023). "Drugging IGF-1R in cancer: New insights and emerging opportunities". Genes & Diseases. 10 (1): 199–211. doi:10.1016/j.gendis.2022.03.002. PMC   10066341 . PMID   37013053.
  6. ↑ Gombos A, Metzger-Filho O, Dal Lago L, Awada-Hussein A (December 2012). "Clinical development of insulin-like growth factor receptor--1 (IGF-1R) inhibitors: at the crossroad?". Investigational New Drugs. 30 (6): 2433–2442. doi:10.1007/s10637-012-9811-0. PMC   3484277 . PMID   22415797.
  7. ↑ "Dalotuzumab". SEER*Rx Interactive Antineoplastic Drugs Database. National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services. Retrieved 2023-01-01.
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