Synthetic carbohydrate-based anticancer vaccines: the Memorial Sloan-Kettering experience

Abstract

SummaryMalignantly transformed cells can express aberrant cell surface glycosylation patterns, which serve to distinguish them from normal cells. This phenotype provides an opportunity for the development of carbohydrate-based vaccines for cancer immunotherapy. Synthetic carbohydratebased vaccines, properly introduced through vaccination of a subject with a suitable construct, should be recognized by the immune system. Antibodies induced against these carbohydrate antigens could then participate in the eradication of carbohydrate-displaying tumor cells. Advances in carbohydrate synthetic capabilities have allowed us to efficiently prepare a range of complex, synthetic anticancer vaccine candidates. We describe herein the progression of our longstanding carbohydrate-based anticancer vaccine program, which is now at the threshold of clinical evaluation in several contexts. Our carbohydrate-based anticancer vaccine program has evolved through a number of stages: (1) monomeric vaccines; (2) monomeric clustered vaccines; (3) unimolecular multi-antigenic vaccines; (4) dual acting vaccines. This account will focus on our recently developed unimolecular multi-antigenic constructs and potential dual-acting constructs, which contain clusters of both carbohydrate and peptide epitopes.

Cancer vaccines and carbohydrate epitopes

“…Aberrant glycosylation is a hallmark of cancer cell transformation. A number of TACA have been described including the mucin related (O-linked) Tn, Sialyl Tn, and Thomsen-Friedenreich antigens, the blood group Lewis related Lewis Y , Sialyl Lewis X , Sialyl Lewis A , and Lewis X (stage-specific embryonic antigen-1, SSEA-1), the glycosphingolipids Globo H, stage-specific embryonic antigen-3 (SSEA-3), and the sialic acid containing glycosphingolipids, the gangliosides GM2, GD2, GD3 and fucosyl GM1 [6,7,8,9,10] (Figure 1a and b). Many of these TACA also are expressed in fetal tissue, and are called oncofetal antigens.…”

Natural Product-Based Drug Discovery

“…It has been predicted that the once-popular natural products used to treat cancers will make a come-back [2][3][4][5], and this has led to extensive discussions on the future of anticancer drug discovery [6]. One useful approach to cancer chemotherapy has been the development of microtubulestabilizing natural products [7], while the use of nanoparticles of natural drugs have been discussed [8], in addition to anticancer vaccines [9]. Anticancer natural products identified since the 1960s have been reviewed [4,5], as have those developed after 2000 [3].…”

Auf dem Weg zur automatisierten Oligosaccharid‐ Synthese

“…Je nach Zahl und Art der Kohlenhydratepitope, die an ein Trägerprotein gekuppelt werden, kann man Strategie (a) weiter unterteilen in 1) monovalente Impfstoffe mit einem Typ von TACAs, 2) monovalente Cluster mit einem Typ von TACAs und 3) unimolekulare polyvalente Konstrukte mit mehreren Typen von TACAs. [306] Vollsynthetische Konjugate tragen Epitope aus 4) zwei Komponenten, 5) drei Komponenten und 6) vier Komponenten. In diesem Teil des Aufsatzes werden wir den erfolgreichsten kohlenhydratbasierten Tumorimpfstoff mit ausgewählten TACAs zusammenfassen.…”

“…In diesem Teil des Aufsatzes werden wir den erfolgreichsten kohlenhydratbasierten Tumorimpfstoff mit ausgewählten TACAs zusammenfassen. Aktuelle Übersichtsartikel über dieses Thema von Boons, [307] Guo, [308] Danishefsky, [306] Ragupathi [309] Oligosaccharid-Synthese…”