Toward optimized carbohydrate-based anticancer vaccines: Epitope clustering, carrier structure, and adjuvant all influence antibody responses to Lewis^yconjugates in mice

Abstract

The feasibility of using carbohydrate-based vaccines for the immunotherapy of cancer is being actively explored at the present time. Although a number of clinical trials have already been conducted with glycoconjugate vaccines, the optimal design and composition of the vaccines has yet to be determined. Among the candidate antigens being examined is Lewis y (Le y ), a blood grouprelated antigen that is overexpressed on the majority of human carcinomas. Using Le y as a model for specificity, we have examined the role of epitope clustering, carrier structure, and adjuvant on the immunogenicity of Le y conjugates in mice. A glycolipopeptide containing a cluster of three contiguous Le y -serine epitopes and the Pam3Cys immunostimulating moiety was found to be superior to a similar construct containing only one Le y -serine epitope in eliciting antitumor cell antibodies. Because only IgM antibodies were produced by this vaccine, the effect on immunogenicity of coupling the glycopeptide to keyhole limpet hemocyanin was examined; although both IgM and IgG antibodies were formed, the antibodies reacted only with the immunizing structure. Reexamination of the clustered Le y -serine Pam3Cys conjugate with the adjuvant QS-21 resulted in the identification of both IgG and IgM antibodies reacting with tumor cells, thus demonstrating the feasibility of an entirely synthetic carbohydrate-based anticancer vaccine in an animal model.

A Fully Synthetic Therapeutic Vaccine Candidate Targeting Carcinoma-Associated Tn Carbohydrate Antigen Induces Tumor-Specific Antibodies in Nonhuman Primates

“…In previous attempts, fully synthetic lipoglycopeptides with a dimeric Tn associated with a palmitoyl core induced IgM but failed to elicit IgG antibodies required for antibodydependent cellular cytotoxicity (ADCC) against cancer cells (29). The same strategy developed with the carcinoma-associated Lewis y antigen also resulted in the sole IgM antibody production (30). In many cases, KLH glycoconjugates also induced IgM antibodies but no or moderate IgG in mice and humans (4).…”

Treatment of autoimmune diabetes in NOD mice by Toll-like receptor 2 tolerance in conjunction with dipeptidyl peptidase 4 inhibition

“…The DPP4 inhibitor is one of the most popular drugs for the management of type 2 diabetes in the clinic. Pam3CSK 4 has also been used without specific side effects for the vaccination of cattle [44] and experimental animals [45,46] and also in patients [47]. Thus, the method described here may provide a novel modality that could be applied in the clinic for the treatment of established type 1 diabetes without the issues associated with islet transplantation.…”

Robust immune responses elicited by a fully synthetic three-component vaccine

“…Thus, immunizations with a liposomal preparation of the individual components of 2 will not require such processing and hence may lead to even more robust antigenic responses. The influence of covalent attachment of the various components of the vaccine candidate on antigenic responses was investigated by immunizing mice with a liposomal preparation of compounds 8b, which is composed of the T-epitope linked to the B-epitope and the adjuvant Pam 3 CysSK 4 (9). Significantly lower titers of IgG antibodies were determined compared to the use of 2 (Table 1).…”

“…In addition, foreign carrier proteins such as keyhole limpet hemocyanin (KLH) and bovine serum albumin (BSA) and the linker that attach the saccharides to the carrier protein can elicit strong B-cell responses, which may lead to the suppression of antibody responses against the carbohydrate epitope 5,6 . It is clear that the successful development of carbohydrate-based cancer vaccines requires novel strategies for the more efficient presentation of tumor-associated carbohydrate epitopes to the immune system, resulting in a more efficient class switch to IgG antibodies [7][8][9][10][11][12][13][14][15][16][17] .…”