Cancer Vaccine Is Best in Class

VACCINE RESEARCH

Some cancer cells express unique carbohydrate antigens that aren't produced by normal cells, and carbohydrate vaccines that can elicit antibodies against these antigens have long been sought as preventive or therapeutic agents. Success, however, has been limited.

A three-part synthetic carbohydrate cancer vaccine has now been developed that elicits a stronger type of antibody response than has been obtained by earlier two-part carbohydrate cancer vaccine candidates. The three-part design may be applicable to other carbohydrate anticancer vaccines and perhaps to carbohydrate antibacterial vaccines as well.

Carbohydrates alone have limited immunogenicity, so researchers conjugate them with immunogenic proteins and add separate adjuvants (immune boosters) to their formulations to improve their antibody-inducing capabilities. Two-part (carbohydrate-protein) conjugates have been used for decades as effective antibacterial vaccines. But carbohydrate-conjugate vaccines directed against cancer have primarily elicited IgM, a weak type of antibody produced by immune system B cells in their initial response to an antigen.

Powerful vaccines instead elicit mostly IgG, the major disease-fighting type of antibody, which is generated in a second-level response only after immune system helper T cells have become activated. But it's been difficult to get synthetic carbohydrate vaccines directed against cancer to induce strong IgG responses.

Chemistry professor Geert-Jan Boons of the Complex Carbohydrate Research Center of the University of Georgia, Athens, and coworkers have now synthesized the first three-component synthetic carbohydrate anticancer vaccine and have demonstrated that it elicits primarily IgG antibodies (Angew. Chem. Int. Ed., published online Aug. 18, www3.interscience.wiley.com/cgi-bin/abstract/111081079).

The vaccine consists of Tn antigen, an oligosaccharide expressed by cancer cells exclusively; a peptide antigen known to activate T cells; and a lipopeptide that acts as an adjuvant and eases packaging of the conjugate into liposomes, a popular vaccine delivery vehicle. The researchers synthesized all three components and then coupled them together. They tested the conjugate in mice, where it elicited predominantly IgG (but also some IgM) antibodies against the Tn antigen.

Key to the advance was the use of a small peptide antigen (instead of a protein) and the three-part design, which is synthetically difficult.

"This is an important accomplishment in that it incorporates an established peptide antigen with a carbohydrate antigen in hopes of generating a dual-action vaccine"--one that elicits a dual IgM-IgG response, comments chemistry professor Samuel J. Danishefsky of Memorial Sloan-Kettering Cancer Center and Columbia University. "It is potentially a real advance," he adds. Danishefsky and coworkers prepared the first generation of synthetic carbohydrate anticancer vaccines about five years ago.

Professor of chemistry and chemical biology Robert J. Linhardt of Rensselaer Polytechnic Institute, Troy, N.Y., notes that "glycoconjugate vaccines have been the quest of a number of laboratories," but the anticancer ones have so far not shown strong helper T cell-dependent responses. With their "cleverly designed glycoconjugate," Boons and coworkers "see five to 15 times as much IgG as IgM, suggesting that they may have solved the fundamental problem of weak glycoconjugate vaccines," Linhardt says. "While other derivatives containing Tn clusters will undoubtedly need to be synthesized prior to initiating clinical studies, the glycoconjugate shows amazingly good properties."

Chemistry professor David R. Bundle of the University of Alberta, Edmonton, says the new fully synthetic vaccine "is an interesting finding that may have future potential," but he notes that the concentrations of the induced antibodies were relatively low and that further verification of the vaccine's in vivo activity will be needed.

Boons's group is now studying improvements and applications of three-part vaccines.