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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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111In-Labeled lexatumumab

, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD 20894

Created: ; Last Update: May 20, 2009.

Chemical name:111In-Labeled lexatumumab
Abbreviated name:111In-EC-HGS-ETR2
Agent Category:Antibody
Target:Tumor necrosis factor–related apoptosis-inducing ligand receptor 2 (TRAILR2)
Target Category:Receptor
Method of detection:Single-photon emission computed tomography (SPECT); gamma planar imaging
Source of signal / contrast:111In
  • Checkbox In vitro
  • Checkbox Rodents
Click here for the nucleotice, protein and gene information regarding TRAIL receptors.



Although anti-growth factor antibodies (Abs) are available for the treatment of cancers (1-3), another technique under investigation to treat this disease is the use of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) receptor (TRAIL-R) agonist Abs such as mapatumumab and lexatumumab (4, 5). These antibodies (Abs) activate a complex apoptotic pathway in the tumor cell, thereby inducing cell death. The apoptotic pathway and the four TRAIL-R types in humans (designated 1 through 4) have been described in detail by Johnstone et al. (4) and Ashkenazi (5). Lexatumumab (TRM-2 or HGS-ETR2) is a TRAIL-R2 monoclonal antibody (mAb) that targets TRAIL-R2; it is under commercial development and has been approved for clinical trials by the United States Food and Drug Administration (USFDA) to treat various cancers. A similar mAb, mapatumumab (TRM-1 or HGS-ETR1), is a TRAIL-R2 mAb that acts as an agonist specifically for the TRAIL-R2 and has been approved by the USFDA for clinical trials.

Paclitaxel and docetaxel are anti-cancer drugs that inhibit the mitosis and proliferation of cells by interfering with the depolymerization of microtubules. The mechanism of action of these drugs was discussed in detail by Saloustros et al. (6). Gong et al. observed that the anti-tumor activity of HGS-ETR1 could be enhanced in mice bearing colorectal cancer cell xenograft tumors with pretreatment with paclitaxel (7). Using HGS-ETR2 labeled with radioactive indium (111In) (111In -EC-HGS-ETR2), the investigators determined that the activity of HGS-ETR2 was increased because the pretreatment with paclitaxel upregulated the expression of TRAIL-R2 in Colo205 cell xenograft tumors in nude mice.



The synthesis of 111In-EC-HGS-ETR2 was described by Gong et al. (7). Briefly, ethylenedicysteine (EC) was coupled to HGS-ETR2 for the chelation of 111In using sulfo-N-hydroxysuccinimide (NHS) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) as the coupling agents. To do this, EC, NHS, and EDC were mixed with HGS-ETR2 and incubated for 17 h at room temperature. The product, EC-HGS-ETR2, was dialyzed (buffer not described) to remove any unbound reagents. The number of EC per HGS-ETR2, the purification and the yield of EC-HGS-ETR1 was not reported by the investigators. Labeling of EC-HGS-ETR2, to obtain 111In-EC-HGS-ETR2, was done performed by adding [111In]-indium chloride to a solution of EC-mAb. The purification and yield of the radiolabeled product were not reported. Although the radiochemical purity of 111In-EC-HGS-ETR2 was reported to be >95% (determined with radio thin-layer chromatography), the specific activity of the labeled mAb was not reported.

For use as controls during scintigraphic imaging, 111In-EC-bovine serum albumin (BSA) and 111In-EC-isotype control mAb were also generated as described above (7).

In Vitro Studies: Testing in Cells and Tissues


The steady state levels of TRAIL-R1 and TRAIL-R2 were determined in Colo205 (a human colorectal cancer tumor cell line) and PA-1 (a human ovarian cancer cell line) cells using immunoblots and fluorescence-activated cell sorting (FACS) (7). Both receptor types were expressed in the two cell lines as determined with the immunoblots, but the levels were reported to be higher in the Colo205 cells than in the PA-1 cells. Similar results were obtained with FACS analysis of the two cell lines.

The concentration for 50% inhibition of cell proliferation (IC50) for Colo205 cells was determined to be 800 ng/mL and 150 ng/mL for HGS-ETR1 and HGS-ETR2, respectively (7). The PA-1 cells were reported to be resistant to inhibition by both the Abs even at a concentration of 800 ng/mL. This indicated that the number of TRAIL-R1 and -R2 on the PA-1 cell surface was too low to initiate apoptosis on binding of the two respective agonist TRAIL-R mAbs.

Animal Studies



Gong et al. studied the tumor uptake of 111In-EC-HGS-ETR2 was studied in nude mice bearing Colo205 xenograft tumors (7). Imaging studies were performed 12 days after inoculation with the cells when the tumor diameter was ~1 cm. The animals (4 or 5 mice/group) were intravenously (IV) injected with either 111In-EC-HGS-ETR2, 111In-EC-BSA, or the 111In-EC-isotype control mAb, and scintigraphic images were obtained 2, 24, and 48 h later. Using computer-outlined regions of interest, the counts per pixel of the tumor site and the normal muscle were used to obtain the tumor/muscle count density ratios (TM ratio). At 2 h after administration of the radiochemicals, little difference in the TM ratios was noted between the controls and the 111In-EC-HGS-ETR2–treated animals. However, at 24 and 48 h after the injection of radioactivity, the TM ratios for the 111In-EC-HGS-ETR2 and the labeled control-injected animals were reported to be ~3.5–4.5 and ~2, respectively.

In another study, the Colo205 cell xenograft tumor–bearing animals (n = 3 mice) were imaged before and after (at 2 and 24 h after an IV injection of 111In-EC-HGS-ETR2) treatment with paclitaxel (7). Animals treated with paclitaxel were imaged 24 h after administration of the drug. When imaging was performed at 2 h after treatment with the labeled mAb, little difference in the TM ratio (~2) was noted in the tumors with or without the paclitaxel treatment. By 24 h the TM ratio was reported to have increased to ~4.2 in tumors of mice treated with paclitaxel compared with a TM ratio of ~2 in the untreated mice. In the same study, PA-1 cell xenograft tumors in animals (n = 3 mice) showed little change in the TM ratio (~1.5) both at 2 and 24 h after the 111In-EC-HGS-ETR2 injection. This indicated that very little of the labeled mAb bound to the tumors derived from the PA-1 cells. No blocking studies were reported and the difference in the TM ratios appeared to be stastically small.

Other Non-Primate Mammals


No references are currently available.

Non-Human Primates


No references are currently available.

Human Studies


No references are currently available.

Supplemental Information



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