Progress Made Toward an Antitumor Vaccine

Researchers have found a way to induce the body to use its own weapon, the immune system, to fight cancer by the same means used against infectious diseases: immunization.

The production of a selective vaccine is not an easy task, however. A team led by Dr. Horst Kunst from the University of Mainz (Germany) has now found a way to bind a molecule that is typical for tumors to a carrier protein without irritating the immune system. As the investigators reported in online June 4, 2007, issue of the journal Angewandte Chemie, their method is based on an immunocompatible connection by way of a sulfur atom called a thioether.

Epithelial tumor cells have unusually large amounts of mucin MUC1 on their surface. This MUC1, in comparison with its "normal” cousins, is also modified in a very characteristic manner. Mucins are mucilaginous substances that protect the surfaces of mucus membranes. They are lipoproteins, which are macromolecules with a central protein chain and long side chains made of polysaccharides. The modified MUC1 would be a good target molecule (antigen) for antibodies in immunologic antitumor therapy.

The difficulty with this approach is that such sugar-containing compounds are completely ineffective at triggering the immune system to form antibodies. Immunization is only successful if the vaccine is anchored to an immunizing carrier protein by means of a spacer,” explained Dr. Kunz. This would be very simple to achieve with polysaccharides, but turns out to be very complicated with glycoproteins, because the protein portion of the molecule has many reactive groups that are attacked in the coupling reaction. "In addition,” commented Dr. Kunz, "many of the structures that make suitable anchors are themselves highly immunogenic, which can suppress the immune response against the true target, the glycoprotein.”

The team has now found a suitable anchoring technique: Their anchor is a thioether (two carbon atoms coupled together through a sulfur atom). To achieve this, the carrier protein is first equipped with a spacer, which has an allyl group (two carbon atoms attached by a double bond) at its end. The glycopeptide is coupled to a building block that causes thiols (sulfur--hydrogen groups) to protrude from the molecule. In the next, light-initiated (photochemical) reaction, only the desired thioether bonds are formed--no side reactions occur at other locations in the peptide chain.

"Synthetic glycopeptide antigens containing structural elements typical of tumors in the sugar as well as the protein segment,” explained Dr. Kunz, "can thus be attached to the carrier protein in a controlled fashion. The largely nonimmunogenic thioether bridges could clear the way for the development of vaccines for immunization against tumor cells.”


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University of Mainz