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Significance of erbB-2 gene product as a target molecule for cancer therapy
T Ishida1, M Tsujisaki, Y Hanzawa
1Department of Internal Medicine, Sapporo Medical University, Japan.
Abstract:
The new monoclonal antibodies (MoAbs) E401, E811, E907 and E919 were prepared and characterized. These recognized an extracellular domain (amino acids No. 292-370) on the human c-erbB-2 gene product. Utilizing MoAb E811 and MoAb E919, a double determinant immunoassay (DDIA) was established to detect the soluble and the shed forms of the c-erbB-2 molecule. The levels of circulating erbB-2 antigen in the sera of patients with benign diseases and healthy controls were very low. The incidence of positivity for shed c-erbB-2 antigen in gastric cancer, colonic cancer, gall-bladder cancer, pancreatic cancer and other cancers were 7.4%, 4.2%, 0%, 6.7% and 0%, respectively. Four of 54 patients with gastric carcinoma showed high levels of serum c-erbB-2 antigen. They belonged to clinical stage IV and their histological types were all well differentiated adenocarcinomas (two papillary and two tubular adenocarcinomas). Furthermore, the incidence of positive staining in gastric cancer was 34.6%; higher than that for shedding erbB-2 antigen. Most of the cases which showed erbB-2 expression on cells were well-differentiated adenocarcinomas. Meanwhile, the distribution of erbB-2 antigen was limited in normal tissues. The results suggest that the expression of erbB-2 antigen is largely restricted to adenocarcinoma cells. It may not shed easily from these cells, and therefore it may be a very useful target molecule for passive immunotherapy.
Insights
New monoclonal antibodies (MoAbs) target the c-erbB-2 protein. A double determinant immunoassay detects shed c-erbB-2 antigen, showing low levels in healthy individuals but elevated levels in some gastric cancers, suggesting it as a potential immunotherapy target.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- The human c-erbB-2 gene product is a significant target in cancer research.
- Understanding the expression and shedding of c-erbB-2 is crucial for developing diagnostic and therapeutic strategies.
Purpose of the Study:
- To develop and characterize new monoclonal antibodies (MoAbs) against the c-erbB-2 protein.
- To establish a sensitive immunoassay for detecting soluble and shed forms of c-erbB-2.
- To investigate the presence of shed c-erbB-2 antigen in various cancers and its correlation with tumor characteristics.
Main Methods:
- Preparation and characterization of four new MoAbs (E401, E811, E907, E919) recognizing an extracellular domain of c-erbB-2.
- Development of a double determinant immunoassay (DDIA) using MoAb E811 and MoAb E919.
- Analysis of serum samples from patients with benign diseases, healthy controls, and various cancer types for shed c-erbB-2 antigen levels.
- Evaluation of c-erbB-2 antigen expression in gastric cancer tissues.
Main Results:
- The developed MoAbs recognize an extracellular domain of the human c-erbB-2 gene product.
- The DDIA effectively detects soluble and shed c-erbB-2. Circulating erbB-2 antigen levels were low in benign diseases and healthy controls.
- Positive results for shed c-erbB-2 antigen were observed in 7.4% of gastric cancer, 4.2% of colonic cancer, and 6.7% of pancreatic cancer cases.
- Four of 54 gastric carcinoma patients (clinical stage IV, well-differentiated adenocarcinomas) showed high serum c-erbB-2 levels.
- Positive c-erbB-2 staining in gastric cancer tissues (34.6%) was higher than shedding antigen detection, with expression predominantly in well-differentiated adenocarcinomas and limited in normal tissues.
Conclusions:
- The expression of erbB-2 antigen is largely restricted to adenocarcinoma cells.
- Shed c-erbB-2 antigen may not be easily released from tumor cells, limiting its utility as a widespread diagnostic marker.
- The restricted expression of c-erbB-2 on cancer cells suggests its potential as a valuable target for passive immunotherapy.