Dalotuzumab

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]

Dalotuzumab
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
TargetIGF-1 receptor
Clinical data
ATC code
  • none
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG
ECHA InfoCard100.205.569
Chemical and physical data
FormulaC6528H10086N1730O2018S40
Molar mass146374.99 g·mol−1
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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. 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. 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. "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. Saygin D, Tabib T, Bittar HE, Valenzi E, Sembrat J, Chan SY, et al. (March 2022). "Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension". Pulmonary Circulation. 10 (1). doi:10.1016/j.gendis.2022.03.002. PMC 7052475. PMID 32166015.
  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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