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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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Humanized anti–type 1 insulin-like growth factor receptor monoclonal antibody conjugated to Alexa 680

AVE1642-Alexa 680
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD 20894

Created: ; Last Update: August 4, 2009.

Chemical name:Humanized anti–type 1 insulin-like growth factor receptor monoclonal antibody conjugated to Alexa 680
Abbreviated name:AVE1642-Alexa 680
Synonym:
Agent Category:Antibody
Target:Type 1 insulin-like growth factor receptor (IGF1R)
Target Category:Receptor
Method of detection:Near-infrared (NIR) fluorescence
Source of signal / contrast:Alexa 680
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Structure not available in PubChem.

Background

[PubMed]

Overexpression and activation of the type 1 insulin-like growth factor receptor (IGF1R), which mediates its activity through an associated tyrosine kinase, is believed to promote the progression and metastasis of several cancers (1-3). In addition, higher than normal or overexpression of the IGF1R itself, or any of its different constituent parts, is considered to indicate an aggressive or drug-resistant cancer phenotype with a poor prognosis for the patient (3). As a consequence, the IGF1R is a target of various agents, including monoclonal antibodies (mAbs) directed against it, that are under evaluation in clinical trials approved by the United States Food and Drug Administration for the treatment of cancers. Also, using xenograft tumor models, a downregulation in IGF1R expression has been shown to be accompanied by reduced tumor growth, suggesting that IGF1R levels can be used to monitor patient response to anti-cancer treatment(s) (4, 5).

The epidermal growth factor receptor (EGFR), which is known to be overexpressed in several cancers, is routinely quantified in a clinical setting using in situ hybridization or immunohistochemical techniques for biopsy samples, and the data obtained from these investigations are used to select patients who are most likely to benefit from an anti-EGFR therapy (6, 7). However, no such quantification is available for IGF1R expression, which has been quantified only in cultured cells using a humanized anti-IGF1R mAb (AVE1642) conjugated to cadmium telluride quantum dots (AVE1642 QD) (8). Zhang et al. developed and evaluated the use of Alexa 680 (a near-infrared fluorescent dye with a maxima at 705 nm) covalently linked to AVE1642 (AVE1642-Alexa 680) in a mouse model for the detection and imaging of xenograft tumors that express IGF1R (9). For comparison the investigators also evaluated the use of AVE1642 QD (discussed in a separate chapter of MICAD; www.micad.nih.gov) for the detection and imaging of the tumors expressing IGF1R (9).

Synthesis

[PubMed]

The AVE1642 mAb was obtained from a commercial source, and its fluorescent labeling was performed with a commercially available Alexa 680 kit according to manufacturer instructions (9). The conjugate was purified with size-exclusion chromatography on a Superdex G200 column as described by Zhang et al. (9). The number of Alexa 680 molecules conjugated to each mAb molecule and the stability of the complex under in vitro or in vivo conditions were not reported.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

The receptor binding ability of AVE1642-Alexa 680 was investigated using MCF-7 cells, a breast cancer cell line that expresses high levels of IGF1R (9). The cells were exposed to AVE1642-Alexa 680, Alexa 680 alone (control), and an anti-CD20 antibody conjugated to Alexa 680 (negative control) for 1 h at 4°C in phosphate-buffered saline (PBS) containing 1% bovine serum albumin and 0.1% sodium azide. Binding of the fluorescent mAbs or the Alexa 680 alone was analyzed with fluorescence-assisted cell sorting (FACS). Only cells exposed to AVE1642-Alexa 680 were reported to bind to the MCF-7 cells.

In another study, mouse embryo fibroblast R cells (lacking the IGF1R gene) transfected with the IGF1R (R-/IGF1R cells) were shown with FACS analysis to bind AVE1642-Alexa 680 (9). Pretreatment of the R-/IGF1R cells with AVE1642 for 24 h was reported to eliminate the binding of AVE1642-Alexa 680 to the cells, indicating that the conjugated mAb bound specifically to the IGF1R.

Animal Studies

Rodents

[PubMed]

Zhang et al. used athymic mice bearing xenograft tumors generated with either R-/IGF1R or MCF-7 cells to investigate the in vivo specificity of AVE1642-Alexa 680 (9). Mice bearing R-/IGF1R tumors were injected with 0.1 nmol conjugated mAb through the tail vein (control animals were injected with PBS alone), and whole-body imaging of the animals was performed at 2 h, 5 h, and 1, 2, 4, and 10 days after the treatment (the number of animals used per time point was not reported). After 1 day, Alexa 680–specific fluorescence was observed only in tumors of animals treated with AVE1642-Alexa 680, with the signal lasting for at least 4 days and diminishing by day 10. However the degree of reduction in signal was not reported by the investigators. No fluorescence was observed in the control animals or in any other organs or tissues of mice injected with the AVE1642 conjugate. Ex vivo imaging of the tumors, organs, and tissues confirmed that the fluorescent signal was present only at the tumor sites.

To confirm that the fluorescence observed in the tumor-bearing animals was only from the conjugated mAb, mice bearing MCF-7 tumors were injected with either AVE1642-Alexa 680 or the anti-CD20 antibody conjugated to Alexa 680 through the tail vein. The number of animals used per group was not specified (9). Whole-body imaging was performed on the animals after 2 days, and a fluorescent signal was observed only in tumors of mice injected with AVE1642-Alexa 680. Presence of the fluorescent signal at the tumor sites was confirmed with ex vivo imaging of the tumors.

In another study, mice bearing R-/IGF1R tumors were pretreated with 200 μg AVE1642 (injected intraperitoneally), and 2 days later the animals were injected with AVE1642-Alexa 680. Control animals were not pretreated with the anti-IGF1R mAb.The number of animals used per agent group was not provided (9). Exposure of IGF1R-positive tumors to AVE1642 was shown by Sachdev et al. to downregulate the number of receptors on the tumor cells (10), and this was reflected by the reduced fluorescence, compared with controls, observed with the tumors pre-exposed to AVE1642.

From these studies the investigators concluded that AVE1642-Alexa 680 could be used to detect and quantify IGF1R in rodents under in vivo conditions (9).

Other Non-Primate Mammals

[PubMed]

No references are currently available.

Non-Human Primates

[PubMed]

No references are currently available.

Human Studies

[PubMed]

No references are currently available.

Supplemental Information

[Disclaimer]

No information is currently available.

References

1.
McCampbell A.S., Broaddus R.R., Loose D.S., Davies P.J. Overexpression of the insulin-like growth factor I receptor and activation of the AKT pathway in hyperplastic endometrium. Clin Cancer Res. 2006;12(21):6373–8. [PubMed: 17085648]
2.
Yuen J.S., Akkaya E., Wang Y., Takiguchi M., Peak S., Sullivan M., Protheroe A.S., Macaulay V.M. Validation of the type 1 insulin-like growth factor receptor as a therapeutic target in renal cancer. Mol Cancer Ther. 2009;8(6):1448–59. [PubMed: 19509240]
3.
Hewish M., Chau I., Cunningham D. Insulin-like growth factor 1 receptor targeted therapeutics: novel compounds and novel treatment strategies for cancer medicine. Recent Pat Anticancer Drug Discov. 2009;4(1):54–72. [PubMed: 19149688]
4.
Goetsch L., Gonzalez A., Leger O., Beck A., Pauwels P.J., Haeuw J.F., Corvaia N. A recombinant humanized anti-insulin-like growth factor receptor type I antibody (h7C10) enhances the antitumor activity of vinorelbine and anti-epidermal growth factor receptor therapy against human cancer xenografts. Int J Cancer. 2005;113(2):316–28. [PubMed: 15386423]
5.
Shang Y., Mao Y., Batson J., Scales S.J., Phillips G., Lackner M.R., Totpal K., Williams S., Yang J., Tang Z., Modrusan Z., Tan C., Liang W.C., Tsai S.P., Vanderbilt A., Kozuka K., Hoeflich K., Tien J., Ross S., Li C., Lee S.H., Song A., Wu Y., Stephan J.P., Ashkenazi A., Zha J. Antixenograft tumor activity of a humanized anti-insulin-like growth factor-I receptor monoclonal antibody is associated with decreased AKT activation and glucose uptake. Mol Cancer Ther. 2008;7(9):2599–608. [PubMed: 18790743]
6.
Meche A., Cimpean A.M., Raica M. Immunohistochemical expression and significance of epidermal growth factor receptor (EGFR) in breast cancer. Rom J Morphol Embryol. 2009;50(2):217–21. [PubMed: 19434314]
7.
Martin V., Mazzucchelli L., Frattini M. An overview of the epidermal growth factor receptor fluorescence in situ hybridisation challenge in tumour pathology. J Clin Pathol. 2009;62(4):314–24. [PubMed: 19052028]
8.
Zhang H., Sachdev D., Wang C., Hubel A., Gaillard-Kelly M., Yee D. Detection and downregulation of type I IGF receptor expression by antibody-conjugated quantum dots in breast cancer cells. Breast Cancer Res Treat. 2009;114(2):277–85. [PubMed: 18418709]
9.
Zhang H., Zeng X., Li Q., Gaillard-Kelly M., Wagner C.R., Yee D. Fluorescent tumour imaging of type I IGF receptor in vivo: comparison of antibody-conjugated quantum dots and small-molecule fluorophore. Br J Cancer. 2009;101(1):71–9. [PMC free article: PMC2713715] [PubMed: 19491901]
10.
Sachdev D., Singh R., Fujita-Yamaguchi Y., Yee D. Down-regulation of insulin receptor by antibodies against the type I insulin-like growth factor receptor: implications for anti-insulin-like growth factor therapy in breast cancer. Cancer Res. 2006;66(4):2391–402. [PubMed: 16489046]

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