Chemistry:Dalotuzumab

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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]

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

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. ↑ 1.0 1.1 1.2 "Dalotuzumab, a recombinant humanized mAb targeted against IGFR1 for the treatment of cancer". Current Opinion in Molecular Therapeutics 12 (3): 361–371. June 2010. PMID 20521225. 
  2. ↑ 2.0 2.1 "The adverse events profile of anti-IGF-1R monoclonal antibodies in cancer therapy". British Journal of Clinical Pharmacology 77 (6): 917–928. June 2014. doi:10.1111/bcp.12228. PMID 24033707. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 "Dalotuzumab Overview". Creative Biolabs. https://www.creativebiolabs.net/dalotuzumab-overview.htm. 
  4. ↑ "Emerging therapies for advanced gastroenteropancreatic neuroendocrine tumors". Clinical Colorectal Cancer 10 (4): 298–309. December 2011. doi:10.1016/j.clcc.2011.06.006. PMID 21813338. 
  5. ↑ 5.0 5.1 5.2 5.3 "Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension". Pulmonary Circulation 10 (1). March 2022. doi:10.1016/j.gendis.2022.03.002. PMID 32166015. 
  6. ↑ "Clinical development of insulin-like growth factor receptor--1 (IGF-1R) inhibitors: at the crossroad?". Investigational New Drugs 30 (6): 2433–2442. December 2012. doi:10.1007/s10637-012-9811-0. PMID 22415797. 
  7. ↑ "Dalotuzumab" (in en). SEER*Rx Interactive Antineoplastic Drugs Database. National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services. https://seer.cancer.gov/seertools/seerrx/rx/53c44afd102c1290262dc57c/?drug_direction=DOWN&regimen_direction=UP&rx_type=drug&drug_field=primary_site&regimen_field=name&drug_offset=100&regimen_offset=450&limit=100&search_mode=&q=&mode=. 



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