Stable GM3 lactone mimetic raises antibodies specific for the antigens expressed on melanoma cells.
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.
Arcangeli
Annarosa
A
Dipartimento di Patologia e Oncologia Sperimentali, Universita' di Firenze, Florence, Italy. annarosa.arcangeli@unifi.it
Toma
Lucio
L
Contiero
Luca
L
Crociani
Olivia
O
Legnani
Laura
L
Lunghi
Carlotta
C
Nesti
Elisa
E
Moneti
Gloriano
G
Richichi
Barbara
B
Nativi
Cristina
C
D000818:Animals; D000906:Antibodies / Q000737:chemistry / Q000276:immunology*; D000918:Antibody Specificity; D000937:Antigen-Antibody Reactions; D002236:Carbohydrate Conformation; D003198:Computer Simulation; D005679:G(M3) Ganglioside / Q000031:analogs & derivatives* / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D006433:Hemocyanins / Q000737:chemistry / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D051379:Mice; D018716:Molecular Mimicry / Q000235:genetics / Q000276:immunology*
D000906:Antibodies; D005679:G(M3) Ganglioside; D006433:Hemocyanins; C047143:ganglioside GM3 lactone; C032808:keyhole-limpet hemocyanin