Efficient Syntheses of ABO Blood Type Antigens Using Diacetyl Strategy and Their Immune Evaluation

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Efficient Syntheses of ABO Blood Type Antigens Using Diacetyl Strategy and Their Immune Evaluation

Masato Tsutsui 1 , Yoshiyuki Manabe 1,2 , Koichi Fukase 1,2

1 Graduate School of Science, Osaka University, Machikaneyama 1-1, Toyonaka, Japan, 2 Core for Medicine and Science Collaborative Research and Education, Project Research Center for Fundamental Science Osaka University, Machikaneyama 1-1, Toyonaka, Japan

ABO blood type is categorized by the oligosaccharide structures on the surface of the red blood cells (Figure a). ABO blood type antigens cause a strong immune response in blood transfusions. We synthesized ABO blood type antigens using diacetyl strategy. Immune response of the synthesized glycans was investigated to develop the novel immune cancer therapy.

ABO blood type antigens contain N-acetyl glucosamine (GlcNAc). Existence of NHAc groups in glycosylation substrates greatly reduces the reactivity due to the formation of intermolecular hydrogen bond. Thus, we proposed "diacetyl strategy", in which NHAc group was protected as NAc2 group during glycosylation. Because NAc2 group cannot form hydrogen bond, the reactivity of glycosylation can be improved by using diacetyl strategy. We have employed diacetyl strategy for the syntheses of Neu5Ac containing glycans. Here, we applied this strategy to synthesis of ABO blood type antigens including GlcNAc.

Aggregation of N-acetylated 4 via hydrogen bond through NHAc was first confirmed by 1HNMR and DOSY spectrum. Chemical shift of amide proton of 4 was shifted to downfield depending on concentration and temperature. The estimated effective volume (V) of N-acetylated 4 (V4 = 1.49×10^-26 m^3) was 1.2 times bigger than that of N-diacetylated 5 (V5 = 1.24×10^-26 m^3), indicating that 4 formed supramolecular structure through intermolecular hydrogen bond and NAc2 derivatives did not aggregate to show enhanced reactivity.

The reactivity of N-acetylated fragment was then compared in the synthesis of O antigen. As expected, diacetyl protection improved the reactivity in both [1+1] and [2+1] glycosylations (Figure B). The enhancement of the reactivity by NAc2 protection was observed in both glycosylations at proximal and distal positions to GlcNAc. We also synthesized A and B type antigens using Troc protected fragments.

We investigated the conjugation of ABO blood type antigens with antibody drugs to enhance the cytotoxicity against tumor cells. These conjugates are expected to induce strong immune response against targeted cells by the action of ABO blood type antigens. After the conjugation with B blood type antigen, we measured CDC activity in the presence of the serum from O blood type person (Figure c). The conjugate can induce CDC activity and its potency was increased as dose-dependent manner.

a) Structure of ABO blood type antigens, b) Glycosylation results, c) Concept of CDC assay

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