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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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IRDye800CW-anti-CD105 TRC105 chimeric monoclonal antibody

IRDye800CW-TRC105
, PhD
National for Biotechnology Information, NLM, NIH, Bethesda, MD

Created: ; Last Update: February 22, 2012.

Chemical name:IRDye800CW-anti-CD105 TRC105 chimeric monoclonal antibody
Abbreviated name:IRDye800CW-TRC105
Synonym:
Agent category:Antibody
Target:CD105 (Endoglin, EDG)
Target category:Antigen
Method of detection:Optical, near-infrared (NIR) fluorescence
Source of signal/ contrast:IRDye 800CW
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on protein, nucleotide (RefSeq), and gene for more information about CD105

Background

[PubMed]

Angiogenesis is an essential process in the development of new blood vessels both in normal physiological states and diseases (1, 2). Targeting of tumor vasculature is a promising strategy for tumor imaging and therapy because tumor growth and metastasis largely depend on angiogenesis (3-5). Transforming growth factor-β (TGF-β) is a pleiotropic cytokine that modulates blood vessel development, angiogenesis, and tumor progression (6). There are three isoforms of TGF-β (β1, β2, and β3). TGF-β1 inhibits proliferation and migration of endothelial cells and their ability to form capillaries. CD105 (endoglin, EDG) is a homodimeric transmembrane glycoprotein (180 kDa) with disulfide-linked subunits of 95,000. CD105 is a component of the TGF-β receptor complex that specifically binds TGF-β1 and TGF-β3 with high affinity (7). CD105 is important for blood vessel development. The expression of CD105 on different cells affects cellular response to TGF-β1. CD105 is overexpressed in proliferating endothelial cells of tumor vessels, and CD105 prevents TGF-β1–mediated inhibition of endothelial cell proliferation (8, 9).

Radiolabeled monoclonal antibodies (mAbs) have been developed for both the diagnosis and treatment of tumors (10-12). Quiescent human endothelial cells express CD105 only weakly, but the expression of CD105 is strongly upregulated on the endothelial cells of tumor tissues undergoing angiogenesis (9, 13). The high level of expressed CD105 (up to 106 molecules/proliferating cell) appears to be ideal for in vivo imaging and therapy. Anti-CD105 mAbs, such as MAEND3, E9, and MJ7/18 with radioisotopes (e.g., 111In, 99mTc, and 125I) have been studied as single-photon emission computed tomography (SPECT) probes for imaging CD105 expression (9, 14). TRC105 is a human/murine chimeric IgG1 mAb that binds with higher affinity to human CD105 than to murine CD105 (15). TRC105 inhibits angiogenesis and tumor growth and is now in clinical trials in cancer patients. Binding of TRC105 to CD105 allows TGF-β1–mediated inhibition of endothelial cell proliferation. Hong et al. (16) showed that 64Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-anti-CD105 TRC105 (64Cu-DOTA-TRC105) mAb could efficiently image 4T1 murine breast tumor in mice with positron emission tomography (PET) imaging. Hong et al. (17) have evaluated 89Zr-desferrioxamine-TRC105 (89Zr-Df-TRC105) as an 89Zr-based PET agent in the same 4T1 murine breast tumor model. For near-infrared (NIR) fluorescence optical imaging, Yang et al. (18) conjugated IRDye800CW to TRC105 to form IRDye800CW-TRC105 to assess CD105 expression in mice bearing 4T1 murine breast tumors.

Synthesis

[PubMed]

Commercially available IRDye800CW-N-hydroxysuccinimide ester (LI-COR, Lincoln, NE) was used to conjugate TRC105 in 1:1 molar ratio to form IRDye800CW-TRC105, which was purified with column chromatography (18). The molar ratio of IRDye800CW to TRC105 in the conjugated antibody was 0.4 with >85% yield. IRDye800CW-cetuximab was also prepared similarly as an isotype-matched control with a similar number of dye molecules per antibody. Cetuximab is an anti-EGFR mouse-human chimeric IgG1 mAb.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Yang et al. (18) performed in vitro indirect fluorescence staining with unlabeled TRC105 and IRDye800CW-TRC105 on MCF7 human breast cancer cells (CD105-negative) and human umbilical vein endothelial cells (HUVECs, CD105-positive). Fluorescence microscopy and flow cytometry showed strong CD105 expression in HUVECs but weak or no expression in MCF7 cells. No significant differences in fluorescence intensities between TRC105 and IRDye800CW-TRC105 were observed in the HUVEC cells, suggesting that IRDye800CW-TRC105 retains immunoreactivity similar to that of the unconjugated mAb.

Animal Studies

Rodents

[PubMed]

Yang et al. (18) studied the accumulation of IRDye800CW-TRC105 using a whole-body fluorescence detection system in mice bearing CD105-positive 4T1 tumors. IRDye800CW-TRC105 (0.3 nmol/mouse) was injected intravenously into mice (n = 3) that showed distinct fluorescence signals in the tumors at 0.5–48 h after injection with a plateau at ~16 h. Regions of interest analysis showed tumor signal levels of 1.91, 1.98, 2.63, 3.70, 5.11, 4.86, and 4.94 × 104 counts/s per mm2 at 0.5, 1, 2, 4, 16, 24, and 48 h after injection, respectively. Pretreatment with TRC105 (13 nmol/mouse, time of pretreatment not reported) significantly (P < 0.05) inhibited the IRDye800CW-TRC105 binding in the tumors by >50% at each time point starting 1 h after injection. IRDye800CW-cetuximab showed tumor signal levels of 0.68, 0.79, 1.29, 1.69, 4.00, 4.23, and 4.37 × 104 counts/s per mm2 at 0.5, 1, 2, 4, 16, 24, and 48 h after injection, respectively. The signals levels of IRDye800CW-cetuximab were lower than those of IRDye800CW-TRC105 at all the time points. The passive accumulation of IRDye800CW-cetuximab at the later time points may be due to the longer circulation half-life of cetuximab (11.5 h) than that of TRC105 (3.5 h). In comparison, IRDye800CW showed significantly (P < 0.05) lower tumor fluorescence signal than IRDye800CW-TRC105 and IRDye800CW-cetuximab at 4–48 h.

Ex vivo NIR fluorescence imaging was performed at 48 h after injection (18). There was a prominent accumulation of IRDye800CW-TRC105 in the liver with some detectable accumulation in the kidneys. The accumulation in tumor was higher than in other major organs except the liver, and accumulation was blocked by pretreatment with TRC105. On the other hand, IRDye800CW-cetuximab exhibited fluorescence signal only in the liver and tumor. The tumor signal was only ~33% of the signal with IRDye800CW-TRC105. Immunofluorescence staining of 4T1 tumor sections showed colocalization of CD31 with CD105 on the tumor endothelial cells (CD31- and CD105-positive) but not on tumor cells (CD31-negative, CD105-positive). On the other hand, there was only a weak CD105 staining on the liver and spleen sections.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

References

1.
Carmeliet P., Jain R.K. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473(7347):298–307. [PMC free article: PMC4049445] [PubMed: 21593862]
2.
Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1(1):27–31. [PubMed: 7584949]
3.
Fonsatti E., Altomonte M., Arslan P., Maio M. Endoglin (CD105): a target for anti-angiogenetic cancer therapy. Curr Drug Targets. 2003;4(4):291–6. [PubMed: 12699349]
4.
Abdollahi A., Folkman J. Evading tumor evasion: current concepts and perspectives of anti-angiogenic cancer therapy. Drug Resist Updat. 2010;13(1-2):16–28. [PubMed: 20061178]
5.
Thorpe P.E. Vascular targeting agents as cancer therapeutics. Clin Cancer Res. 2004;10(2):415–27. [PubMed: 14760060]
6.
Massague J., Cheifetz S., Laiho M., Ralph D.A., Weis F.M., Zentella A. Transforming growth factor-beta. Cancer Surv. 1992;12:81–103. [PubMed: 1638549]
7.
Cheifetz S., Bellon T., Cales C., Vera S., Bernabeu C., Massague J., Letarte M. Endoglin is a component of the transforming growth factor-beta receptor system in human endothelial cells. J Biol Chem. 1992;267(27):19027–30. [PubMed: 1326540]
8.
Tabata M., Kondo M., Haruta Y., Seon B.K. Antiangiogenic radioimmunotherapy of human solid tumors in SCID mice using (125)I-labeled anti-endoglin monoclonal antibodies. Int J Cancer. 1999;82(5):737–42. [PubMed: 10417773]
9.
Bredow S., Lewin M., Hofmann B., Marecos E., Weissleder R. Imaging of tumour neovasculature by targeting the TGF-beta binding receptor endoglin. Eur J Cancer. 2000;36(5):675–81. [PubMed: 10738134]
10.
Wu A.M., Senter P.D. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol. 2005;23(9):1137–46. [PubMed: 16151407]
11.
Milenic D.E., Brechbiel M.W. Targeting of radio-isotopes for cancer therapy. Cancer Biol Ther. 2004;3(4):361–70. [PubMed: 14976424]
12.
Kowalsky, R.J., S.W. Falen, Radiopharmaceutcals in nuclear pharmacy and nuclear medicine. Second ed. 2004, Washington, D.C.: APhA. 733-752.
13.
Seon B.K., Haba A., Matsuno F., Takahashi N., Tsujie M., She X., Harada N., Uneda S., Tsujie T., Toi H., Tsai H., Haruta Y. Endoglin-targeted cancer therapy. Curr Drug Deliv. 2011;8(1):135–43. [PubMed: 21034418]
14.
Fonsatti E., Jekunen A.P., Kairemo K.J., Coral S., Snellman M., Nicotra M.R., Natali P.G., Altomonte M., Maio M. Endoglin is a suitable target for efficient imaging of solid tumors: in vivo evidence in a canine mammary carcinoma model. Clin Cancer Res. 2000;6(5):2037–43. [PubMed: 10815930]
15.
Tsujie M., Tsujie T., Toi H., Uneda S., Shiozaki K., Tsai H., Seon B.K. Anti-tumor activity of an anti-endoglin monoclonal antibody is enhanced in immunocompetent mice. Int J Cancer. 2008;122(10):2266–73. [PubMed: 18224682]
16.
Hong H., Yang Y., Zhang Y., Engle J.W., Barnhart T.E., Nickles R.J., Leigh B.R., Cai W. Positron emission tomography imaging of CD105 expression during tumor angiogenesis. Eur J Nucl Med Mol Imaging. 2011;38(7):1335–43. [PMC free article: PMC3105181] [PubMed: 21373764]
17.
Hong, H., G.W. Severin, Y. Yang, J.W. Engle, Y. Zhang, T.E. Barnhart, G. Liu, B.R. Leigh, R.J. Nickles, and W. Cai, Positron emission tomography imaging of CD105 expression with (89)Zr-Df-TRC105. Eur J Nucl Med Mol Imaging, 2011. [PMC free article: PMC3228902] [PubMed: 21909753]
18.
Yang Y., Zhang Y., Hong H., Liu G., Leigh B.R., Cai W. In vivo near-infrared fluorescence imaging of CD105 expression during tumor angiogenesis. Eur J Nucl Med Mol Imaging. 2011;38(11):2066–76. [PMC free article: PMC3189267] [PubMed: 21814852]
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