Immunotherapy for cancer: synthetic carbohydrate-based vaccines

Disulfideand Multisulfide-Containing Metabolites from Marine Organisms Cheng-Shi Jiang, Werner E. G. M€uller, Heinz C. Schr€oder, and Yue-Wei Guo* State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang High-Tech Park, Shanghai 201203, People’s Republic of China Institute for Physiological Chemistry, Medical Center of the Johannes Gutenberg-University, Duesbergweg 6, D-55128 Mainz, Germany

Disulfide- and multisulfide-containing metabolites from marine organisms.

Carbohydrates have established themselves as the most clinically relevant antigens of those tested and subsequently developed for vaccines against infectious diseases. However, in cancer patients, many of the defined carbohydrate antigens are really altered 'self' antigens and for unclear reasons, the body does not react to them immunologically. Although these self antigens have been found to be potentially suitable targets for immune recognition and killing, the development of vaccines for cancer treatment is actually more challenging compared with those for infectious diseases mainly because of the difficulty associated with breaking the body's immunological tolerance to the antigen. These antigens lack the inherent immunogenicity associated with bacterial antigens and, therefore, methods to enhance immunological recognition and induction of immunity in vivo are under investigation. These include defining the appropriate tumour-associated antigen, successfully synthesizing the antigen to mimic the original molecule, inducing an immune response, and subsequently enhancing the immunological reactivity so that all components can work together. This has been successfully accomplished with several glycolipid and glycoprotein antigens using carriers such as keyhole limpet haemocyanin (KLH) together with a saponin adjuvant, QS-21. Not only can high titre IgM and IgG antibodies be induced, which are specific for the antigen used for immunization, but the antibodies can mediate complement lysis. The approaches for synthesis, conjugation, clinical administration and immunological potential are discussed.

Carbohydrate vaccines as immunotherapy for cancer

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 group-related 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 Pam(3)Cys 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 Pam(3)Cys 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.

https://www.pnas.org/content/pnas/98/6/3264.full.pdf

Toward optimized carbohydrate-based anticancer vaccines: epitope clustering, carrier structure, and adjuvant all influence antibody responses to Lewis(y) conjugates in mice

Carbohydrates and Immunology: Synthetic Oligosaccharide Antigens for Vaccine Formulation

Total synthesis of the novel benzopentathiepin varacinium trifluoroacetate: the viability of "varacin-free base"

Application of the Glycal Assembly Method to the Concise Synthesis of Neoglycoconjugates of Ley and Leb Blood Group Determinants and of H-Type I and H-Type II Oligosaccharides

Clay catalyzed rearrangement of substituted allyl phenyl ethers: Synthesis of ortho-allyl phenols, chromans and coumarans

The photochemistry of ten 1,5-hexadien-3-ones in methanol is studied over the wavelength range of 313-366 nm, by using monochromatic light. With the goal of understanding the unusual wavelength-dependent selectivity observed for 5-methyl-1,5-hexadien-3-one (1), quantum yield measurements, structure reactivity studies, triplet sensitization, and quenching experiments are performed. While six of the ten dienones studies show selectivities that are independent of irradiation wavelength from 313 to 366 nm, four of the dienones exhibit wavelength-dependent selectivities that are similar to that observed in 1, thus establishing that 1 is not unique, a spreviously believed. Triplet sensitization studies suggest that the wavelength dependence results, largely,, from a single-state α-cleavage reaction that completes with triplet cycloaddition. A variety of triplet quenchers were ineffective as inhibiting these reactions. Some possible mechanisms are discussed

Victor Behar

Papers

Total synthesis of the novel benzopentathiepin varacinium trifluoroacetate: the viability of "varacin-free base"

Application of the Glycal Assembly Method to the Concise Synthesis of Neoglycoconjugates of Ley and Leb Blood Group Determinants and of H-Type I and H-Type II Oligosaccharides

Clay catalyzed rearrangement of substituted allyl phenyl ethers: Synthesis of ortho-allyl phenols, chromans and coumarans

Photochemistry of 1,5-hexadien-3-ones : wavelength-dependent selectivity in intramolecular enone-olefin photoadditions

Wavelength dependent photoisomerization of bicyclo[3.1.0]hexenones