Tumor-associated glycoprotein 72

Discovery

Researchers identified Tumor-associated glycoprotein 72 (TAG-72) in the mid-1980s during the development of the Monoclonal antibody B72.3. These antibodies selectively bound to a high-molecular-weight glycoprotein found on various Carcinoma cells. Later studies confirmed TAG-72 as a Mucin-like molecule with significant Glycosylation, which adds to its high molecular weight. This discovery has supported advancements in cancer diagnostics and therapeutics, especially those targeting TAG-72-expressing tumors.

Structure

TAG-72 is a high-molecular-weight glycoprotein(1,000 Kda), primarily expressed on the surface of various Adenocarcinomas. Its structure is features extensive O-linked glycosylation, which gives it a mucin-like configuration. The glycosylation patterns of TAG-72 include tumor-associated carbohydrate antigens such as sialyl-Tn (STn) and Thomsen–Friedenreich antigens, which are contribute to tumor progression and metastasis. These carbohydrate epitopes serve as binding sites for monoclonal antibodies like B72.3 and CC49, enabling targeted cancer detection and treatment.

Pathogenic mechanism

TAG-72 rarely appears in normal adult tissues but is highly present in malignant epithelial cells, which makes it a Tumor-specific antigen. It plays a role in:

• Tumor Progression: TAG-72 forms part of the mucinous barrier that shields tumor cells from immune recognition.
• Cell Adhesion and Metastasis: Its Glycosylation influences how tumor cells interact with the extracellular matrix, facilitating metastasis.

Clinical applications

1. Tumor Marker (CA 72-4 Assay)

TAG-72 is commonly measured with radioimmunoassays like CA 72-4, which uses the monoclonal antibodies indium (111In) satumomab pendetide and iodine (125I) minretumomab. This assay has a good specificity for gastric cancer, with a correlation to the neoplasia's extension. It is used for:

• Cancer diagnosis and staging
• Monitoring recurrence and therapy effectiveness
• Targeted Cancer Therapies

Since TAG-72 is tumor-specific, it is a promising target for immunotherapy and antibody-drug conjugates:

• Monoclonal Antibody Therapy:
  • Minretumomab (CC49) has been studied for targeting TAG-72 in solid tumors.
  • Anatumomab mafenatox is an anti-TAG-72 antibody conjugated with toxins for cancer treatment.
• CAR-T Cell Therapy: CAR-T cells engineered to recognize TAG-72 have been tested in ovarian and colorectal cancer.

Cancer association

TAG-72 is mainly found in epithelial-derived malignancies, including:

Gastrointestinal

• Colorectal cancer: TAG-72 is overexpressed in colorectal Adenocarcinoma, and serum levels often reflect tumor stage and prognosis
• Gastric cancer: CA 72-4, an immunoassay detecting TAG-72, is widely used for diagnosing and monitoring gastric cancer.
• Pancreatic cancer: TAG-72 levels have helped in diagnosing late stage pancreatic cancers.

Gynecological

• Ovarian cancer: TAG-72 expression correlates with tumor stage and patient prognosis.

Other cancers

• Lung cancer: TAG-72 is present in a subset of non-small cell lung carcinomas.
• Breast cancer: Although less specific, TAG-72 has been detected in certain aggressive breast cancer subtypes.

References

References

1. (2007-06-28). "Expression of TAG-72 in ovarian cancer and its correlation with tumor stage and patient prognosis". Cancer Letters.
2. (2018-11-19). "Effective Targeting of TAG72+ Peritoneal Ovarian Tumors via Regional Delivery of CAR-Engineered T Cells". Frontiers in Immunology.
3. (2021-01-16). "Engineered CAR-T cells targeting TAG-72 and CD47 in ovarian cancer". Molecular Therapy Oncolytics.
4. (2017-03-21). "Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer". Journal for Immunotherapy of Cancer.
5. [http://www.cancer.gov/dictionary?CdrID=45925 TAG-72 antigen] entry in the public domain NCI Dictionary of Cancer Terms
6. (Mar 2012). "Antibody therapy of cancer". Nature Reviews. Cancer.
7. (Dec 1988). "Purification and Composition of the Human Tumor-associated Glycoprotein (TAG-72) Defined by Monoclonal Antibodies CC49 and B72.3". Cancer Research.
8. (2021-12-07). "Survival Advantage Following TAG-72 Antigen-Directed Cancer Surgery in Patients With Colorectal Carcinoma: Proposed Mechanisms of Action". Frontiers in Oncology.
9. (2023). "Measuring the multifaceted roles of mucin-domain glycoproteins in cancer". Advances in Cancer Research.
10. Chopra, Arvind. (2004). "99mTc-Labeled tumor-associated glycoprotein 72 binding peptides A2-6 and A3-10". National Center for Biotechnology Information (US).
11. (2023-01-06). "The (Sialyl) Tn antigen: Contributions to immunosuppression in gastrointestinal cancers". Frontiers in Oncology.
12. (June 2019). "Cancer-associated mucins: role in immune modulation and metastasis". Cancer and Metastasis Reviews.
13. (2019). "Altered Cell Adhesion and Glycosylation Promote Cancer Immune Suppression and Metastasis". Frontiers in Immunology.
14. (1992-03-01). "CA 72-4 measurement of tumor-associated glycoprotein 72 (TAG-72) as a serum marker in the management of gastric carcinoma". Cancer Research.
15. (2004). "Serum HCG beta and CA 72-4 are stronger prognostic factors than CEA, CA 19-9 and CA 242 in pancreatic cancer". Oncology.
16. (October 2002). "Serum HCG beta, CA 72-4 and CEA are independent prognostic factors in colorectal cancer". International Journal of Cancer.
17. (October 2004). "Preoperative hCGbeta and CA 72-4 are prognostic factors in gastric cancer". International Journal of Cancer.
18. (2002). "Preoperative serum levels of CA 72-4, CEA, CA 19-9, and alpha-fetoprotein in patients with gastric cancer". Revista do Hospital das Clinicas.
19. (November 1996). "Correlation between tumor-associated glycoprotein 72 mucin levels in tumor and serum of colorectal patients as measured by the quantitative CA 72-4 immunoassay". Cancer Research.
20. (1991). "Clinical evaluation of the new tumor marker TAG-72". Anticancer Research.
21. "Anti-TAG-72 [Minretumomab (CC49 )]".
22. "Anti-Human TAG-72 Recombinant Antibody(Anatumomab Mafenatox) - KMD Bioscience-Nanobody Discovery Platform, Protein Expression Systems, and CRO Service Supplier".
23. (2021-03-26). "Engineered CAR-T cells targeting TAG-72 and CD47 in ovarian cancer". Molecular Therapy Oncolytics.
24. (January 2019). "The prognostic role of tumor associated glycoprotein 72 (TAG-72) in stage II and III colorectal adenocarcinoma". Pathology, Research and Practice.
25. (2021-12-01). "The application of CA72-4 in the diagnosis, prognosis, and treatment of gastric cancer". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer.
26. (June 1994). "Clinical value of serum TAG-72 as a tumor marker for pancreatic carcinoma. Comparison with CA 19-9". International Journal of Pancreatology.
27. (2007-06-28). "Expression of TAG-72 in ovarian cancer and its correlation with tumor stage and patient prognosis". Cancer Letters.
28. (2008-12-08). "A new TAG-72 cancer marker peptide identified by phage display". Cancer Letters.
29. (2002). "Differential TAG-72 epitope expression in breast cancer and lymph node metastases: a marker of a more aggressive phenotype". Oncology Reports.