Alternate immunization strategies to provide protective immunity to a tumor-associated antigen TF-Ag
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The Thomsen-Friedenreich Antigen (TF-Ag) is a carbohydrate tumor associated antigen which is hidden on normal cell membranes due to the addition of other sugar units which cover it. It is known to play a major role in the metastatic spread of cancer cells. The JAA-F11 monoclonal antibody, created by Dr. Rittenhouse-Olson et al ., decreases metastasis in vivo by blocking adhesion to the blood vessels so that the tumor cells do not get into other organs. The JAA-F11 antibody significantly extended the survival time of animals with metastatic 4T1 breast tumors and reduced lung metastasis. It is hypothesized that active immunization, in order to have the patient make their own antibody to TF-Ag will create a survival advantage for patients with TF-Ag expressing tumors by direct killing of the tumor cells, blocking of tumor cell adhesion and inhibition of metastasis. For vaccine development, synthetic gold nanoparticles were coated with TF-Ag-MUC4 glycopeptides and C3d N-terminal peptides for immunization. The mice were injected with the vaccine preparation and blood samples for antibody analysis were collected biweekly. The samples were tested against the synthetic TF-Ag-MUC4 containing compounds, TF-Ag BSA and asialofetuin, a naturally occurring molecule with TF-Ag. The resultant antibodies have also been tested in vitro for the ability to kill the 4T1 mouse breast tumor cells by cell-mediated cytotoxicity and complement-dependent cytotoxicity mechanisms. Finally, the in vivo ability of the immunized mice to protect against 4T1 mouse breast tumor cells was measured by determining the degree of lung metastasis and survival studies after implanting the 4T1 tumor cells into the mouse mammary gland. The prime focus of this research was to develop active immunotherapy to provide protection from recurrence of breast cancer. One of the TF-MUC4 gold nanoparticle constructs was shown to not only reduce metastasis but also to increase survival in mice with breast tumor. Therefore, TF-Ag has great potential in cancer therapeutics and continued research with TF-MUC4#3 should focus on efficient delivery of synthetic TF-Ag glycoconjugates, in combination with interleukins or other cytokines, for protection against breast cancer and its recurrence. It is important to note however, that two of the other TF-MUC4 gold nanoparticle constructs worsened the in vivo results in tumor bearing mice. The position of the TF-Ag and the amount of TF-Ag per gold nanoparticle may be of critical importance in the development of any therapeutic.