Background

[PubMed]

Tumor-associated glycoprotein 72 (TAG-72) is a high molecular weight mucigenous protein that is found mainly in the extracellular matrix of neoplastic tumors (1). This glycoprotein is usually not expressed in normal tissues, but it is overexpressed in the tumors of several cancers, such as those of the colon and rectum (colorectal cancer), stomach, pancreas, ovaries, prostate, lung, breast, etc. Therefore, TAG-72 is considered to have a great deal of theranostic value (useful for the diagnosis and/or therapy of a disease) because it can be used for antigen-directed surgical resection of cancerous tumors with radiolabeled anti-TAG-72 monoclonal antibodies (mAb) (1). In addition, the detection or absence of TAG-72 expression in colorectal cancer tumors has been shown to have a prognostic value because individuals who had complete removal of tumors with surgery guided by mouse anti-TAG-72 mAb were shown to have a long-term survival advantage compared to patients who had incomplete removal of the lesions (2). In an effort to develop diagnostic agents that can be used for the rapid detection of tumors that overexpress TAG-72, investigators developed a ¹²⁵I-labeled complimentary determining region–grafted humanized C_H2-domain-deleted anti-TAG-72 mAb ([¹²⁵I]-HuCC49deltaC_H2) and showed that it can be used in preclinical (mouse model) and human clinical settings to detect xenograft colorectal cancer tumors positive for TAG-72 (3). In the human studies, the ¹²⁵I-labeled mAb was used in conjunction with a hand-held gamma detection probe that assisted the surgeon to precisely locate and resect the tumor, which resulted in improved prognosis for the patient (4).

However, the main limitation of using ¹²⁵I to develop a targeted tracer is that this radionuclide has a long half-life (~60 days) and is difficult to handle, store, and dispose from the hospital operating room (4). In addition, it is not the most suitable radionuclide for diagnostic imaging because it is a low-energy gamma emitter and generates low-quality images with scintigraphy. Therefore, as an alternative, investigators have used ¹²⁴I to produce various types of imaging probes (small molecules, proteins antibodies, etc.) because it has a half-life of ~4 days, emits β particles that yield superior images with positron emission tomography (PET), and is easier to handle, store, and dispose. On the basis of this information, Zou et al. labeled HuCC49deltaC_H2 with ¹²⁴I ([¹²⁴I]-HuCC49deltaC_H2) and in a preliminary study evaluated the ¹²⁴I-labeled mAb for the detection of LS174T colon adenocarcinoma cell xenograft tumors (that express high levels of TAG-72) with PET in nude mice (4).

Synthesis

[PubMed]

The Iodogen method was used for the ¹²⁴I labeling of HuCC49deltaC_H2 conjugated to 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid as described by Zou et al. (4). The radiochemical yield of the labeled mAb was reported to be 98%. The radiochemical purity, specific activity, and stability of [¹²⁴I]-HuCC49deltaC_H2 was not reported. The tracer was filtered through a 0.22-micron filter for in vivo use.

For use as a control, a commercially available preparation of ¹⁸F-labeled fluorodeoxyglucose ([¹⁸F]-FDG; 200 MBq/mL (5.4 Ci/mL)) was used to detect the xenograft tumors in the animals (4)

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Slavin-Chiorini et al. reported that HuCC49deltaC_H2 inhibited the binding of mouse CC49 (muCC49) and HuCC49 to the TAG-72 antigen (5). The relative affinity constants (K_d) of HuCC49deltaC_H2, HuCC49, and muCC49 were determined to be 5.1 nM, 2.1 nM, and 2.3 nM, respectively.

Animal Studies

Human Studies

[PubMed]

No publication is currently available.

Supplemental Information

[Disclaimers]

No supplemental information is currently available.

NIH Support

Studies presented in this chapter were supported in part by National Cancer Institute grant R01 CA120023.

References

1.

Povoski S.P., Hatzaras I.S., Mojzisik C.M., Martin E.W. Oncologic theranostics: recognition of this concept in antigen-directed cancer therapy for colorectal cancer with anti-TAG-72 monoclonal antibodies. Expert Rev Mol Diagn. 2011;11(7):667–70. [PubMed: 21902525]

2.

Povoski, S.P., I.S. Hatzaras, C.M. Mojzisik, M.W. Arnold, G.H. Hinkle, C.L. Hitchcock, D.C. Young, and E.W. Martin, Jr., Antigen-Directed Cancer Surgery for Primary Colorectal Cancer: 15-Year Survival Analysis. Ann Surg Oncol, 2011. [PubMed: 21732140]

3.

Cheng, K.T., Radioiodinated anti-TAG-72 humanized CH2 domain-deleted antibody. Molecular Imaging and Contrast agent Database (MICAD) [database online]. National Library of Medicine, NCBI, Bethesda, MD, USA. Available from www​.micad.nih.gov, 2004 -to current. [PubMed: 20641585]

4.

Zou P., Povoski S.P., Hall N.C., Carlton M.M., Hinkle G.H., Xu R.X., Mojzisik C.M., Johnson M.A., Knopp M.V., Martin E.W. Jr, Sun D. 124I-HuCC49deltaCH2 for TAG-72 antigen-directed positron emission tomography (PET) imaging of LS174T colon adenocarcinoma tumor implants in xenograft mice: preliminary results. World J Surg Oncol. 2010;8:65. [PMC free article: PMC2924340] [PubMed: 20691066]

5.

Slavin-Chiorini D.C., Kashmiri S.V., Lee H.S., Milenic D.E., Poole D.J., Bernon E., Schlom J., Hand P.H. A CDR-grafted (humanized) domain-deleted antitumor antibody. Cancer Biother Radiopharm. 1997;12(5):305–16. [PubMed: 10851481]