Dalotuzumab (MK-0646; h7C10), being developed by Merck & Co Inc under license from Pierre Fabre SA, is a recombinant humanized IgG1 mAb against the IGF1R for the potential intravenous treatment of cancer, including Breast Cancer, Non-Small Cell Lung Cancer, and Metastatic Colorectal Cancer.
In multiple cancer cell lines and in mouse xenograft models, dalotuzumab displayed significant antitumor activity, in particular against NSCLC and breast cancer. In addition, coadministration of dalotuzumab with other anticancer agents, such as taxanes, enhanced the in vitro and in vivo antitumor activity of dalotuzumab. Preliminary data from phase I clinical trials suggest that dalotuzumab is a safe drug, which is well tolerated and significantly inhibits tumor proliferation. Several clinical trials evaluating dalotuzumab, alone and in combination with other anticancer agents, were ongoing in patients with various types of solid tumor and in patients with multiple myeloma. Although preliminary results appear promising, only future clinical and translational data will clarify the best clinical setting and treatment combinations for the optimal use of dalotuzumab in clinical practice. A randomized phase II/III study for metastatic colorectal cancer, adding dalotuzumab to irinotecan and cetuximab was feasible but did not improve survival outcome.
The insulin family of growth factors is an evolutionally conserved system which plays a crucial role in the growth and development of many tissues and the regulation of overall growth and metabolism. This system comprises three receptors [insulin receptor (IR), IGF-1 receptor (IGF-1R), and IGF-2/mannose 6-phosphate receptor (M-6-PR)], three ligands (insulin, IGF-1, and IGF-2), and six known types of circulating IGF-binding proteins (IGFBP1-6). The IGF-1R is highly homologous to the IR.
The IGF-1R is a receptor tyrosine kinase with a structure of a heterotetrameric glycoprotein composed of two α and two β subunits, post-transcriptionally linked by disulfide bonds, which regulates cell survival and cell cycle progression via the PI3K/Akt and extracellular signal regulated kinase pathways through insulin receptor substrate-1to-4 (IRS-1to-4) and Src-homology collagen (Shc) adapter proteins. Phosphorylation of the IRS adapter molecules on one hand triggers activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, whereas, on the other hand, the Shc adapter activates signaling by the Ras/Raf/MEK/Erk signaling pathway. IGF-IR seems to be expressed in most human cancers. The two IGF-1R ligands, IGF-1 and IGF-2, have been implicated in cancer initiation and progression.
In the past decades, a large amount of evidence has emphasized that IGF-IR play a key role in the transformation of cells, cancer cell proliferation, as well as in metastatic events, associated in various types of human cancers. It seems that inhibition of IGF-IR signaling can generate antineoplastic effects. A number of monoclonal antibodies have been developed to target the receptor itself, which bind to the extracellular domains of the IGF-1R and block ligand binding. A feature common to all anti-IGF-1R antibodies, probably more important than the blocking activity itself, is their ability to down-regulate of the IGF-1R overtime by promoting internalization of the receptor. Receptor targeting antibodies might have important therapeutic advantages, concerning both specificity and toxicity. A variety of fully human anti-IGF-1R monoclonal antibodies have been characterized and showed strong anti-tumor activity in vitro and in vivo.
Dalotuzumab (MK-0646) is one of the fully human monoclonal antibodies against the IGF-1R. Dalotuzumab inhibits ligand (IGF-1, IGF-2) binding to IGF1R and induces receptor internalization and degradation with inhibition of downstream pathway activation.
Figure 1 Mechanism of Action of Dalotuzumab
NCT ID | Status | Conditions | Lead Sponsor | Update Time |
NCT00654420 | Completed | Carcinoma, Non-small-cell Lung | Merck Sharp & Dohme Corp. | April 4, 2017 |
NCT00759785 | Completed | Breast Cancer | Merck Sharp & Dohme Corp. | April 14, 2017 |
NCT00701103 | Completed | Solid Tumor, Multiple Myeloma | Merck Sharp & Dohme Corp. | May 11, 2017 |
NCT00694356 | Completed | Neoplasm | Merck Sharp & Dohme Corp. | June 15, 2017 |
NCT01431547 | Completed | Solid Tumors | Merck Sharp & Dohme Corp. | June 17, 2016 |
NCT00730379 | Completed | Neoplasms | Merck Sharp & Dohme Corp. | February 10, 2015 |
NCT01609231 | Completed | Rectal Neoplasms | Merck Sharp & Dohme Corp. | January 7, 2015 |
NCT00614393 | Completed | Metastatic Colorectal Cancer | Merck Sharp & Dohme Corp. | February 24, 2017 |
NCT00799240 | Completed | Non Small Cell Lung Cancer | University of Kansas | November 7, 2014 |
NCT01243762 | Terminated | Neoplasms Malignant | Merck Sharp & Dohme Corp. | April 11, 2018 |
NCT01234857 | Completed | Breast Cancer | Merck Sharp & Dohme Corp. | May 31, 2017 |
NCT00925015 | Completed | Colorectal Cancer | Merck Sharp & Dohme Corp. | August 2, 2017 |
NCT01605396 | Terminated | Breast Neoplasms | Merck Sharp & Dohme Corp. | April 19, 2018 |
NCT00610129 | Completed | Neuroendocrine Tumors, Metastatic Neuroendocrine Tumors | Memorial Sloan Kettering Cancer Center | November 20, 2015 |
NCT01220570 | Completed | Breast Cancer | Merck Sharp & Dohme Corp. | January 21, 2015 |
NCT00729742 | Completed | Carcinoma, Non-small Cell Lung | Merck Sharp & Dohme Corp. | April 4, 2016 |
NCT01175291 | Withdrawn | Metastatic Colorectal Cancer | H. Lee Moffitt Cancer Center and Research Institute | December 5, 2011 |
NCT00635778 | Completed | Advanced Solid Tumors | Merck Sharp & Dohme Corp. | April 8, 2016 |
NCT00869752 | Completed | Lung Cancer | NCIC Clinical Trials Group | March 7, 2014 |
NCT00903006 | Terminated | Breast Cancer | M.D. Anderson Cancer Center | February 2, 2015 |
NCT00769483 | Active, not recruiting | Pancreatic Cancer, Pancreatic Adenocarcinoma | M.D. Anderson Cancer Center | November 23, 2016 |
NCT00951444 | Withdrawn | Lung Cancer | Alliance for Clinical Trials in Oncology | July 6, 2016 |
NCT02711865 | Not yet recruiting | Ovarian Cancer | Hillel Yaffe Medical Center | March 17, 2016 |
We provide high-quality Dalotuzumab for use in WB, FC, IP, ELISA, Neut, FuncS, IF and most other immunological methods. For lab research use only, not for diagnostic, therapeutic or any in vivo human use.
* The table was excerpted from the following website
https://clinicaltrials.gov/ct2/results?cond=&term=Dalotuzumab&cntry=&state=&city=&dist=
For research use only. Not intended for any clinical use.
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