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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-Capromab pendetide

111In-CYT-356
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD, vog.hin.mln.ibcn@dacim

Created: ; Last Update: May 24, 2008.

Chemical name:111In-Capromab pendetide
Abbreviated name:111In-CYT-356, 111In-GYK-DTPA-7E11-C5.3, 111In-DTPA-7E11-C5.3, 111In-7E11-C5.3
Synonym:ProstaScint®
Agent Category:Antibody
Target:Prostate-specific membrane antigen (PSMA)
Target Category:Antibody-antigen binding
Method of detection:SPECT
Source of signal:111In
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Humans
Click on protein, nucleotide (RefSeq), and gene for more information about PSMA.

Background

[PubMed]

Prostate-specific membrane antigen (PSMA) is a unique type II, transmembrane-bound glycoprotein that is overexpressed on prostate tumor cells and in the neovasculature of most of the solid tumors, but not in the vasculature of normal tissues (1, 2). This unique expression of PSMA makes it an important biomarker as well as a large extracellular target of imaging agents (3, 4). 7E11-C5, a monoclonal antibody against the cytoplasmic domain of PSMA, was found to be specific to prostate tumor tissues in humans when conjugated with glycyl-tyrosyl-(N-ε-diethylenetriamine pentacetic acid)-lysine (GYK-DTPA). Tumors often contain dying or necrotic cells with permeable membranes, allowing the binding of antibodies to the intracellular epitope of PSMA. The antibody conjugate (Capromab pendetide or CYT-365) was radiolabeled with 111Indium. 111In-CYT-356 was approved by the US Food and Drug Administration in 1996 for the detection of prostate carcinoma and soft tissue metastases in prostate cancer patients. Newer antibodies against the extracellular domain of PSMA are being developed for immunotherapy of prostate cancer (5, 6).

Synthesis

[PubMed]

Purified monoclonal antibody 7E11-C5.3 was coupled with GYK-DTPA by site-specifically generated reactive aldehyde groups on the oligosaccharides found on the heavy chain of the antibody (7). A mixture of 111InCl3 (37 MBq, 1 mCi) and the conjugated antibody (100 μg) was incubated for 1 h at 37ºC. 111In-CYT-356 was purified by high performance chromatography (8). The specific activity was 55.5-210.9 MBq/mg (1.5-5.7 mCi/mg).

111In-CYT-356 can be easily prepared from a commercially available kit consisting of two vials to be mixed: 1) a sterile solution of 185 MBq/ml (5 mCi/ml) 111In-choride in sodium acetate buffer; and 2) a sterile solution of 0.5 mg of CYT-356. The mixture was incubated at room temperature for 30 min and filtered through a 0.22-μm filter.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

LNCaP human prostate cancer cells were reported to have a Kd of 6.69 nm with [131I]7E11-C5 and Bmax of 95,000 sites/cell in saturation binding studies (9) using intact cells. The binding was accounted for by a subpopulation of permeated cells produced when the cells were trypsinized and washed. Little internalization of the tracer was found over a period of 48 h at 37ºC. When permeated cells were used, the number of binding sites/cell was similar to [131I]J591, an antibody against the extracellular domain of PSMA. Using nonpermeated cells, [131I]J591 has a Kd of 1.83 nm and a Bmax of 600,000-800,000 sites/cell.

Various immunohistochemical studies indicate that 7E11-C5 reacts weakly with normal prostate epithelial cells and strongly with malignant prostate epithelial cells but does not react with non-prostate tumors or most normal tissues (8, 10-14). It also stains endothelial cells in solid tumors, such as lung, renal, colon, and breast carcinomas but not in normal vascular endothelial cells (15, 16).

Animal Studies

Rodents

[PubMed]

Biodistribution of 111In-CYT-356 was studied in LNCaP tumor-bearing nude mice by ex vivo tissue radioactivity measurements (8). 111In-CYT-356 uptake in tumor was high with 14% injected dose/g (ID/g) on day 1 after injection of 11.7 μg of the tracer (0.59 MBq, 16 μCi). It increased to 30% ID/g on days 3 and 7. Tumor image was visible by scintigraphic scan on day 4. Uptake in the lung, spleen, liver, and kidney was 4-6% ID/g, whereas the muscle showed an uptake of <1% ID/g. Uptake in non-tumor organs was similar in tumor-bearing mice and normal mice. 111In-CYT-356 did not accumulate in PC-3 and Du-145 prostate tumor lines (PSMA negative). Furthermore, 111In-labeled GYK-DTPA-conjugated, nonspecific antibody did not localize to the LNCaP tumor.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

Human dosimetry of 111In-CYT-356 was estimated in 25 prostate cancer patients (17). Dynamic whole-body positron emission tomography (PET) scans were acquired after the injection of 185 MBq (5 mCi) of 111In-CYT-356 over a 7-10-day period. The organ that received the highest absorbed dose was the liver (1.0 mGy/MBq or 3.7 rad/mCi), followed by the spleen (0.88 mGy/MBq or 3.3 rad/mCi), and the kidneys (0.67 mGy/MBq or 2.5 rad/mCi). The prostate was estimated at 0.44 mGy/MBq (1.63 rad/mCi). The effective dose was calculated as 0.25-0.29 mSv/MBq (0.93-1.07 rem/mCi).

In one of the pivotal studies, 111In-CYT-356 scans (152 patients with prostate cancer) had a sensitivity, specificity, and overall accuracy of 62, 72, and 68%, respectively (18). The sensitivity of computed tomography (CT) and magnetic resonance imaging (MRI) was 4% and 15%, respectively.

Sodee et al. (19) reported the results of a retrospective study of 2,290 111In-CYT-356 scans of 2,154 patients with prostate cancer performed at 15 institutions. 111In-CYT-356 scans identified positive uptake in the prostate or fossa (70.4%), pelvic nodes (31.5%), pelvic and extrapelvic nodes (23.9%), and extrapelvic nodes only (11.0%). In patients with newly diagnosed prostate cancer (n = 487), there was a significant correlation (p < 0.001) of prostate-specific antigen (PSA) level with positive 111In-CYT-356 scans in the prostate bed and pelvic metastases. The association between PSA level and positive 111In-CYT-356 scans in the fossa recurrence was weaker (p < 0.033) in patients after surgery (n = 1,225) and was not significant for pelvic and extrapelvic metastases. There was no association between PSA level and 111In-CYT-356 scans in patients with radiation therapy (n = 340) or hormonal therapy (n = 238).

111In-CYT-356 imaging has been studied in the detection of nodal metastases, detection of recurrent prostate cancer, detection of occult extraprostatic fossa, and evaluation before definitive therapy in patients with prostate cancer [PubMed]. Fusion studies of 111In-CYT-356 scans with CT or MRI improve the prediction of lymph node metastases in patients for definitive local therapy (20, 21).

References

1.
Feneley M.R., Jan H., Granowska M., Mather S.J., Ellison D., Glass J., Coptcoat M., Kirby R.S., Ogden C., Oliver R.T., Badenoch D.F., Chinegwundoh F.I., Nargund V.H., Paris A.M., Britton K.E. Imaging with prostate-specific membrane antigen (PSMA) in prostate cancer. Prostate Cancer Prostatic Dis. 2000;3(1):47–52. [PubMed: 12497162]
2.
Ghosh A., Heston W.D. Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer. J Cell Biochem. 2004;91(3):528–39. [PubMed: 14755683]
3.
Nanus D.M., Milowsky M.I., Kostakoglu L., Smith-Jones P.M., Vallabahajosula S., Goldsmith S.J., Bander N.H. Clinical use of monoclonal antibody HuJ591 therapy: targeting prostate specific membrane antigen. J Urol. 2003;170(6 Pt 2):S84–8. [PubMed: 14610416]
4.
Nargund V., Al Hashmi D., Kumar P., Gordon S., Otitie U., Ellison D., Carroll M., Baithun S., Britton K.E. Imaging with radiolabelled monoclonal antibody (MUJ591) to prostate-specific membrane antigen in staging of clinically localized prostatic carcinoma: comparison with clinical, surgical and histological staging. BJU Int. 2005;95(9):1232–6. [PubMed: 15892807]
5.
Bander N.H., Trabulsi E.J., Kostakoglu L., Yao D., Vallabhajosula S., Smith-Jones P., Joyce M.A., Milowsky M., Nanus D.M., Goldsmith S.J. Targeting metastatic prostate cancer with radiolabeled monoclonal antibody J591 to the extracellular domain of prostate specific membrane antigen. J Urol. 2003;170(5):1717–21. [PubMed: 14532761]
6.
Smith-Jones P.M., Vallabhajosula S., Navarro V., Bastidas D., Goldsmith S.J., Bander N.H. Radiolabeled monoclonal antibodies specific to the extracellular domain of prostate-specific membrane antigen: preclinical studies in nude mice bearing LNCaP human prostate tumor. J Nucl Med. 2003;44(4):610–7. [PubMed: 12679407]
7.
Rodwell J.D., Alvarez V.L., Lee C., Lopes A.D., Goers J.W., King H.D., Powsner H.J., McKearn T.J. Site-specific covalent modification of monoclonal antibodies: in vitro and in vivo evaluations. Proc Natl Acad Sci U S A. 1986;83(8):2632–6. [PMC free article: PMC323353] [PubMed: 3458222]
8.
Lopes A.D., Davis W.L., Rosenstraus M.J., Uveges A.J., Gilman S.C. Immunohistochemical and pharmacokinetic characterization of the site-specific immunoconjugate CYT-356 derived from antiprostate monoclonal antibody 7E11-C5. Cancer Res. 1990;50(19):6423–9. [PubMed: 1698122]
9.
Smith-Jones P.M., Vallabahajosula S., Goldsmith S.J., Navarro V., Hunter C.J., Bastidas D., Bander N.H. In vitro characterization of radiolabeled monoclonal antibodies specific for the extracellular domain of prostate-specific membrane antigen. Cancer Res. 2000;60(18):5237–43. [PubMed: 11016653]
10.
Horoszewicz J.S., Kawinski E., Murphy G.P. Monoclonal antibodies to a new antigenic marker in epithelial prostatic cells and serum of prostatic cancer patients. Anticancer Res. 1987;7(5B):927–35. [PubMed: 2449118]
11.
Murphy G.P., Elgamal A.A., Troychak M.J., Kenny G.M. Follow-up ProstaScint scans verify detection of occult soft-tissue recurrence after failure of primary prostate cancer therapy. Prostate. 2000;42(4):315–7. [PubMed: 10679761]
12.
Silver D.A., Pellicer I., Fair W.R., Heston W.D., Cordon-Cardo C. Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res. 1997;3(1):81–5. [PubMed: 9815541]
13.
Sweat S.D., Pacelli A., Murphy G.P., Bostwick D.G. Prostate-specific membrane antigen expression is greatest in prostate adenocarcinoma and lymph node metastases. Urology. 1998;52(4):637–40. [PubMed: 9763084]
14.
Troyer J.K., Beckett M.L., Wright G.L. Detection and characterization of the prostate-specific membrane antigen (PSMA) in tissue extracts and body fluids. Int J Cancer. 1995;62(5):552–8. [PubMed: 7665226]
15.
Liu H., Moy P., Kim S., Xia Y., Rajasekaran A., Navarro V., Knudsen B., Bander N.H. Monoclonal antibodies to the extracellular domain of prostate-specific membrane antigen also react with tumor vascular endothelium. Cancer Res. 1997;57(17):3629–34. [PubMed: 9288760]
16.
Chang S.S., O'Keefe D.S., Bacich D.J., Reuter V.E., Heston W.D., Gaudin P.B. Prostate-specific membrane antigen is produced in tumor-associated neovasculature. Clin Cancer Res. 1999;5(10):2674–81. [PubMed: 10537328]
17.
Mardirossian G., Brill A.B., Dwyer K.M., Kahn D., Nelp W. Radiation absorbed dose from indium-111-CYT-356. J Nucl Med. 1996;37(9):1583–8. [PubMed: 8790224]
18.
Manyak M.J., Hinkle G.H., Olsen J.O., Chiaccherini R.P., Partin A.W., Piantadosi S., Burgers J.K., Texter J.H., Neal C.E., Libertino J.A., Wright G.L., Maguire R.T. Immunoscintigraphy with indium-111-capromab pendetide: evaluation before definitive therapy in patients with prostate cancer. Urology. 1999;54(6):1058–63. [PubMed: 10604708]
19.
Sodee D.B., Malguria N., Faulhaber P., Resnick M.I., Albert J., Bakale G. Multicenter ProstaScint imaging findings in 2154 patients with prostate cancer. The ProstaScint Imaging Centers. Urology. 2000;56(6):988–93. [PubMed: 11113745]
20.
Schettino C.J., Kramer E.L., Noz M.E., Taneja S., Padmanabhan P., Lepor H. Impact of fusion of indium-111 capromab pendetide volume data sets with those from MRI or CT in patients with recurrent prostate cancer. AJR Am J Roentgenol. 2004;183(2):519–24. [PubMed: 15269050]
21.
Wong T.Z., Turkington T.G., Polascik T.J., Coleman R.E. ProstaScint (capromab pendetide) imaging using hybrid gamma camera-CT technology. AJR Am J Roentgenol. 2005;184(2):676–80. [PubMed: 15671397]
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