A Synthetic Vaccine Consisting of a Tumor‐Associated Sialyl‐T<sub>N</sub>‐MUC1 Tandem‐Repeat Glycopeptide and Tetanus Toxoid: Induction of a Strong and Highly Selective Immune Response

Kaiser, Anton; Gaidzik, Nikola; Westerlind, Ulrika; Kowalczyk, Danuta; Hobel, Alexandra; Schmitt, Edgar; Kunz, Horst

doi:10.1002/anie.200902564

Cited by 143 publications

(138 citation statements)

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“…24 The synthesis of the T N -antigen block 5 was carried out by a previously prepared N-acetylgalactosamine-threonine conjugate, 25 which reacted with a glycosyl donor through a variation of the Koenigs-Knorr glycosylation (Scheme 1a). 26 Then the N-acetylgalactosamine-threonine conjugate 4 was produced by the conversion of the azide function into an acetamido group through reductive acetylation.…”

Section: Synthesis Of the Muc1 Glycopeptide Antigen Analoguesmentioning

confidence: 99%

“…30 The synthesis of N-hydroxysuccinimide-11-mercaptoundecanoate (MUDHSE) coordinated gold nanoparticles 14 with a diameter of 7 nm was carried out by a two-step route described in Scheme 2. In the first step dodecanethiol (DT) coordinated gold nanoparticles 12 were prepared by a one-pot synthesis, which was established by Stucky et al 28 In the second step the dodecanethiol ligand was exchanged for the previously prepared N-hydroxysuccinimide-11-mercaptoundecanoate 24 13 by a one step ligand exchange reaction in absolute DMF. To present the MUC1-glycopeptide antigen analogues multivalently, they were coupled to the prepared MUDHSE functionalized nanoparticles.…”

Section: Preparation Of Surface-modified Gold Nanoparticles and The Imentioning

confidence: 99%

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Synthesis of tumor-associated MUC1-glycopeptides and their multivalent presentation by functionalized gold colloids

et al. 2015

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The mucin MUC1 is a glycoprotein involved in fundamental biological processes, which can be found over-expressed and with a distinctly altered glycan pattern on epithelial tumor cells; thus it is a promising target structure in the quest for effective carbohydrate-based cancer vaccines and immunotherapeutics.Natural glycopeptide antigens indicate only a low immunogenicity and a T-cell independent immune response; however, this major drawback can be overcome by coupling of glycopeptide antigens multivalently to immunostimulating carrier platforms. In particular, gold nanoparticles are well suited as templates for the multivalent presentation of glycopeptide antigens, due to their remarkably high surfaceto-volume ratio in combination with their high biostability. In this work the synthesis of novel MUC1-glycopeptide antigens and their coupling to gold nanoparticles of different sizes are presented. In addition, the development of a new dot-blot immunoassay to test the potential antigen-antibody binding is introduced.

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Section: Synthesis Of the Muc1 Glycopeptide Antigen Analoguesmentioning

confidence: 99%

Section: Preparation Of Surface-modified Gold Nanoparticles and The Imentioning

confidence: 99%

Synthesis of tumor-associated MUC1-glycopeptides and their multivalent presentation by functionalized gold colloids

et al. 2015

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“…[2] Noch stärker und hochselektiv fiel die Immunantwort aus, wenn Wildtyp-balb/c-Mäuse mit einer Vakzine behandelt wurden, in der das tumorassoziierte MUC1-Glycopeptid an Tetanustoxoid gebunden ist. [3] Diese Vakzineform hat den Vorteil, dass sie beim Menschen anwendbar wäre. Natürlich wird durch eine MUC1-Tetanustoxoid-Vakzine auch eine starke Immunreaktion gegen das Tetanustoxoid induziert.…”

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Vollsynthetische Vakzinen aus tumorassoziierten MUC1‐Glycopeptiden und einem Lipopeptid‐Liganden des Toll‐like Rezeptors 2

et al. 2010

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“…For example, tumor-selective epitopes could be created with the sialyl-T antigen linked to a specific mucin peptide, which could increase its immunogenicity (30). Therefore, recombinant WbwA O104 could be used to synthesize stereo-and linkagespecific bacterial structures as well as the human sialyl-T antigen for functional studies or development of a tumor-selective vaccine targeting the sialyl-T epitope.…”

Section: Figmentioning

confidence: 99%

Identification and Biochemical Characterization of the Novel α2,3-Sialyltransferase WbwA from Pathogenic Escherichia coli Serotype O104

et al. 2015

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The sialyl-T antigen sialyl␣2-3Gal␤1-3GalNAc is a common O-glycan structure in human glycoproteins and is synthesized by sialyltransferase ST3Gal1. The enterohemorrhagic Escherichia coli serotype O104 has the rare ability to synthesize a sialyl-T antigen mimic. We showed here that the wbwA gene of the E. coli O104 antigen synthesis gene cluster encodes an ␣2,3-sialyltransferase WbwA that transfers sialic acid from CMP-sialic acid to Gal␤1-3GalNAc␣-diphosphate-lipid acceptor. Nuclear magnetic resonance (NMR) analysis of purified WbwA enzyme reaction product indicated that the sialyl-T antigen sialyl␣2-3Gal␤1-3GalNAc␣-diphosphate-lipid was synthesized. We showed that the conserved His-Pro (HP) motif and Glu/Asp residues of two EDG motifs in WbwA are important for the activity. The characterization studies showed that WbwA from E. coli O104 is a monofunctional ␣2,3-sialyltransferase and is distinct from human ST3Gal1 as well as all other known sialyltransferases due to its unique acceptor specificity. This work contributes to knowledge of the biosynthesis of bacterial virulence factors. IMPORTANCEThis is the first characterization of a sialyltransferase involved in the synthesis of an O antigen in E. coli. The enzyme contributes to the mimicry of human sialyl-T antigen and has unique substrate specificity but very little sequence identity to other sialyltransferases. Thus, the bacterial sialyltransferase is related to the human counterpart only by the similarity of biochemical activity. Sialic acids are ubiquitous in nature and contribute to the acidity and hydration of a glycoprotein, metal ion binding, and epitope exposure. Sialylation affects the adhesive properties of cells and has been implicated in the functions of cell surface receptors (1). Sialic acids are also found in O antigens of bacterial lipopolysaccharides (LPS) or lipooligosaccharides, for example, in Neisseria, Campylobacter, Pasteurella, or Photobacterium spp. (2-5). In Escherichia coli, O antigens containing sialic acid linkages are rare and have only been found in serotypes O24, O55, O104, O145, and O171 (ECODAB). Specific proteins in the mammalian nervous system as well as a number of bacterial capsules carry polysialic acids that regulate adhesive properties of the cell. Masking their own antigens with human-like structures derived from glycolipids and glycoproteins may help bacteria to escape the host immune system. For example, Campylobacter jejuni has lipooligosaccharides resembling human gangliosides (2). However, cross-reactivity in infected humans can lead to autoimmune disease affecting the nervous system, for example the Guillain-Barré syndrome (3). O-acetylation of sialic acids controls the exposure of sialyl epitopes (1).The enterohemorrhagic, Shiga toxin-producing E. coli serotype O104 is the causative agent of outbreaks of bloody diarrhea and hemolytic-uremic syndrome with significant mortality (6, 7). The E. coli O104 antigen has the unusual repeating unit structure (DGal␣1-4Neu5,7,9Ac 3 ␣2-3-D-Gal␤1-3-D-GalNAc␤1) n (ECOD...

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A Synthetic Vaccine Consisting of a Tumor‐Associated Sialyl‐T_N‐MUC1 Tandem‐Repeat Glycopeptide and Tetanus Toxoid: Induction of a Strong and Highly Selective Immune Response

Cited by 143 publications

References 38 publications

Synthesis of tumor-associated MUC1-glycopeptides and their multivalent presentation by functionalized gold colloids

Synthesis of tumor-associated MUC1-glycopeptides and their multivalent presentation by functionalized gold colloids

Vollsynthetische Vakzinen aus tumorassoziierten MUC1‐Glycopeptiden und einem Lipopeptid‐Liganden des Toll‐like Rezeptors 2

Identification and Biochemical Characterization of the Novel α2,3-Sialyltransferase WbwA from Pathogenic Escherichia coli Serotype O104

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A Synthetic Vaccine Consisting of a Tumor‐Associated Sialyl‐TN‐MUC1 Tandem‐Repeat Glycopeptide and Tetanus Toxoid: Induction of a Strong and Highly Selective Immune Response

Cited by 143 publications

References 38 publications

Synthesis of tumor-associated MUC1-glycopeptides and their multivalent presentation by functionalized gold colloids

Synthesis of tumor-associated MUC1-glycopeptides and their multivalent presentation by functionalized gold colloids

Vollsynthetische Vakzinen aus tumorassoziierten MUC1‐Glycopeptiden und einem Lipopeptid‐Liganden des Toll‐like Rezeptors 2

Identification and Biochemical Characterization of the Novel α2,3-Sialyltransferase WbwA from Pathogenic Escherichia coli Serotype O104

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A Synthetic Vaccine Consisting of a Tumor‐Associated Sialyl‐T_N‐MUC1 Tandem‐Repeat Glycopeptide and Tetanus Toxoid: Induction of a Strong and Highly Selective Immune Response