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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2011.

Bookshelf ID: NBK83299PMID: 22259814

64Cu-1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid-anti-CD105 TRC105 chimeric monoclonal antibody

64Cu-DOTA-TRC105
Kam Leung, PhD
National for Biotechnology Information, NLM, NIH, Bethesda, MD
MICAD/at/ncbi.nlm.nih.gov

Created: October 27, 2011; Last Update: January 12, 2012.

Chemical name:64Cu-1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid-anti-CD105 TRC105 chimeric monoclonal antibody
Abbreviated name:64Cu-DOTA-TRC105
Synonym:
Agent category:Antibody
Target:CD105 (Endoglin, EDG)
Target category:Antigen
Method of detection:Positron emission tomography (PET)
Source of signal/ contrast:64Cu
Activation:No
Studies:

  • Checkbox In vitro

  • Checkbox Rodents

Click on protein, nucleotide (RefSeq), and gene for more information about CD105

Background

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[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 kDa. 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 endothelium 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 radionuclides (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 bind 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. Hong et al. (16) showed that 64Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-anti-CD105 TRC105 (64Cu-DOTA-TRC105) mAbs could efficiently image 4T1 murine breast tumor in mice with positron emission tomography (PET) imaging.

Synthesis

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[PubMed]

DOTA-TRC105 was prepared as described previously (17). DOTA-TRC105 was purified with column chromatography. The number of DOTA moieties per mAb was not reported. DOTA-TRC105 (0.33 nmol) was incubated with 74 MBq (2 mCi) 64CuCl2 in sodium acetate buffer (pH 6.5) for 30 min at 40°C. 64Cu-DOTA-TRC105 was purified with column chromatography (16). This procedure provided a radiolabeling yield of >90%, with a specific activity of ~224 MBq/nmol (6.1 mCi/nmol) and a radiochemical purity of >98%. There were 0.42 ± 0.04 (n = 3) 64Cu ions per antibody molecule. 64Cu-DOTA-cetuximab was also prepared similarly as an isotype-matched control with similar specific activity. Cetuximab is an anti-EGFR mouse-human chimeric IgG1 mAb.

In Vitro Studies: Testing in Cells and Tissues

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[PubMed]

Hong et al. (16) performed in vitro indirect fluorescence staining with the unlabeled TRC105 and DOTA-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 DOTA-TRC105 were observed in the HUVEC cells, suggesting that DOTA-TRC105 retains immunoreactivity similar to that of the unconjugated mAb.

Animal Studies

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Rodents

[PubMed]

Hong et al. (16) injected 5–10 MBq (0.14–0.27 mCi) 64Cu-DOTA-TRC105 into mice bearing the CD105-positive 4T1 murine breast tumors for ex vivo biodistribution and PET imaging studies (n = 3/group). Ex vivo tumor accumulation was 10% injected dose/gram (ID/g) and 7% ID/g at 24 h and 48 h after injection, respectively. The tumor/muscle ratios were 22.1 ± 1.5 and 25.2 ± 1.2 at 24 h and 48 h, respectively. The organ with the highest accumulation at 24 h was the liver (22% ID/g), followed by the spleen (12% ID/g), kidney (8% ID/g), and lung (4% ID/g). By 48 h, tumor accumulation was higher than that in all major organs. On the other hand, the accumulation of 64Cu-DOTA-cetuximab (control) in most organs was higher than that in the 4T1 tumors at 48 h after injection. The tumor accumulation of 64Cu-DOTA-cetuximab was ~35% of the accumulation of 64Cu-DOTA-TRC105 in the tumor (P < 0.05). 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 weak CD105 staining on the liver and spleen sections. The accumulation of 64Cu-DOTA-TRC105 in the 4T1 tumors was largely CD105 specific, whereas accumulation in the liver and spleen was largely CD105 nonspecific. Using the same tumor model, Yang et al. (18) reported that the circulation half-life of 64Cu-DOTA-TRC105 was 3.5 h and the circulation half-life of 64Cu-DOTA-cetuximab was 11.5 h.

PET imaging revealed estimated tumor accumulation of 8.0 ± 0.5% ID/g, 10.4 ± 2.8% ID/g, and 9.7 ± 1.8% ID/g at 4, 24, and 48 h after injection of 64Cu-DOTA-TRC105 (16), respectively. Accumulation in the liver was 26.6 ± 2.2% ID/g, 12.8 ± 0.7% ID/g, and 9.6 ± 0.6% ID/g at 4, 24, and 48 h, respectively. The radioactivity in the blood was 16.5 ± 1.3% ID/g, 8.0 ± 1.5% ID/g, and 6.5 ± 1.4% ID/g at 4, 24, and 48 h, respectively. The tumor accumulation of 64Cu-DOTA-cetuximab was <2.5% ID/g at 4, 24, and 48 h after injection. Injection of excess TRC105 (13 nmol) 2 h before 64Cu-DOTA-TRC105 inhibited tumor accumulation to the background level (<2% ID/g). The blocking effect of excess TRC105 on other organs was not reported.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

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[PubMed]

No publication is currently available.

References

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1.
Carmeliet P., Jain R.K. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473(7347):298–307. [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.
Cai W., Chen K., He L., Cao Q., Koong A., Chen X. Quantitative PET of EGFR expression in xenograft-bearing mice using 64Cu-labeled cetuximab, a chimeric anti-EGFR monoclonal antibody. Eur J Nucl Med Mol Imaging. 2007;34(6):850–8. [PubMed: 17262214]
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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