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antibody titer tended to be highest in patients with early breast cancer, and to decrease with more advanced disease. However, HER-2/neu was overexpressed in about 25 percent of patients with advanced breast cancer, where it was associated with more aggressive disease. Researchers speculate that the existent immunity occurs early on in the course of disease and prevents the progression of some patients.

Researchers have shown that the antibody response is to the whole protein and to both the intracellular and extracellular domains. This appears to be due to cell breakdown, which releases previously sequestered segments of the protein. The extracellular domain functions as a growth factor receptor, so that when it is amplified and overexpressed, the signalling through this protein is part and parcel of the aggressiveness of the disease. Some monoclonal antibodies to HER-2/neu have agonistic effects, some have antagonistic effects; hence, antibodies to the extracellular domain might either inhibit or stimulate the growth of breast cancer cells.

Researchers studied the patients with the highest antibody titer in greater detail. In several of these patients, the IgG antibody binds to the same tumor cells that overexpress HER-2/neu. Using epitope mapping, they have discovered a segment of the extracellular domain that is rich in cystine and thus a potential binding site. The researchers are now investigating whether this is a functional antibody.

Some patients with an IgG antibody response also showed a proliferative T-cell response to HER-2/neu. The patient with the highest antibody response also had the greatest T-cell response, to both whole protein and to peptides from the intra- and extracellular domains. Other patients showed proliferative response to peptides but not whole protein. Researchers have not yet mapped all of the epitopes involved.

Animal Models. To learn how to immunize with the HER-2/neu protein, researchers needed to develop an animal model. In the mouse, the neu sequence is not evident and has not been closed. Rat neu protein is quite homologous to human HER-2/neu, but when researchers immunized rats with purified neu protein in complete Freund’s adjuvant, they could find neither proliferative T-cell response nor antibody response.

Earlier researchers had developed a vaccinia virus vector that expressed the extracellular domain of rat neu protein. While this vector was immunogenic in mice, however, it too failed to elicit a response in rats. Those researchers had concluded that the failure to elicit a response was due to tolerance to self. However, subsequent screening has identified patients with existent immune response, proving that is possible to overcome tolerance to HER-2/neu.

Researchers therefore began to focus on immunizing to fragments of the protein. They found that immunizing rats with groups of intracellular domain neu peptides resulted in peptide-specific T-cell and antibody responses, and that the T-cells that responded to peptide also responded to whole protein. They were also able to immunize to peptides from the extracellular domain, but the response was much weaker. This may be due to a biological principle—i.e.,



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