Stable GM₃ Lactone Mimetic Raises Antibodies Specific for the Antigens Expressed on Melanoma Cells

Abstract

Immunotherapy of tumors and of melanoma in particular has a long history, and recently this therapeutic approach found a reliable scientific rationale. This biological therapy aims to teach the patient's immune system to recognize the antigens expressed on tumor cells and destroy them, leaving normal cells intact. The success of this therapy highly depends on the selection of target antigens that are essential for tumors growth and progression. The overexpression of GM(3) ganglioside 1 and especially the expression of its metabolite GM(3) lactone 2 characterize murine and human melanomas, playing an important role in tumor progression and making such self-antigens potential targets for the immunotherapy of these neoplasms. Although more immunogenic than its precursor, GM(3) lactone 2 is unsuitable to be used in immunotherapy as a melanoma-associated antigen (MAA) because it is unstable under physiological conditions. We designed and synthesized the hydrolytically stable mimetic 3, which is remarkably simpler than the native lactone 2; after conjugation of 3 to the protein carrier keyhole-limpet hemocyanin (KLH), the obtained glycoprotein 5 was used as the immunogen in vivo to successfully elicit specific antimelanoma antibodies. In fact, no appreciable binding to GM(1) was observed. Capitalizing on the stability and on the reduced structural complexity of mimetic 3, the immunostimulant 5 we report represents a new promising synthetic glycoconjugate for the immunotherapy of melanoma.

Improvement of the immune efficacy of carbohydrate vaccines by chemical modification on the GM3 antigen

“…The carriers include one to many components such as proteins, 3-6 monoclonal antibodies, 7 peptides, [8][9][10][11][12] lipopeptides, 13 liposomes, 6,13 virosomes, 6,14 and zwitterionic polysaccharides, [15][16][17] the last of which are antigens themselves, can stimulate potent Th-cell response, 15,16 and also be used as carriers for other carbohydrate antigens. [20][21][22] Other mimics include the use of clustered antigens 23,24 and the alteration of the individual natural sugar moiety. Some of these mimics were designed to improve stability, by unnatural glycosidic linkages, 18 truncated antigens, 19 or lactone structures.…”

Synthetic Vaccines against Cancers

“…Most of these antigen analogs were found to provide similar, and sometimes stronger, immunological responses with improved resistance against enzymatic degradation and bioavailability. For example, a structurally simple thioether-bridged mimetic [33] of the GM3 lactone is a hydrolytically stable mimetic of a metabolite of the GM3 antigen and was described by Nativi and coworkers ( Fig. 14.8).…”

Recent Development in Carbohydrate Based Anticancer Vaccines

“…Recently, Arcangeli and colleagues reported the design and synthesis of disaccharides to mimic GM3 lactone. [60] After KLH conjugation, the resulting glycoprotein was used for immunization in mice with significant IgM titers obtained against melanoma cells.…”