Chemoenzymatic Synthesis of 9NHAc-GD2 Antigen to Overcome the Hydrolytic Instability of O-Acetylated-GD2 for Anticancer Conjugate Vaccine Development.
Chemoenzymatic Synthesis of 9NHAc-GD2 Antigen to Overcome the Hydrolytic Instability of O-Acetylated-GD2 for Anticancer Conjugate Vaccine Development.
复制标题
化学酶法合成 9NHAc-GD2 抗原克服 O-乙酰化-GD2 的水解不稳定性，用于抗癌结合疫苗的开发
DOI：
10.1002/anie.202108610
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发表时间：
2021-11-02
期刊：
影响因子：
--
通讯作者：
Huang X
中科院分区：
文献类型：
--
作者：
Wu X;Ye J;DeLaitsch AT;Rashidijahanabad Z;Lang S;Kakeshpour T;Zhao Y;Ramadan S;Saavedra PV;Yuzbasiyan-Gurkan V;Kavunja H;Cao H;Gildersleeve JC;Huang X
神经节苷脂GD2是一种很有吸引力的肿瘤相关碳水化合物抗原，可用于抗癌疫苗的开发。然而，它的低免疫原性和抗GD2抗体的显著副作用给疫苗的开发带来了巨大的障碍。为了克服这些问题，设计了一种新的GD2衍生物，其非还原端含有N-乙酰胺(NHAC)神经氨酸(9NHAc-GD2)来模拟9-O-乙酰化GD2(9OAc-GD2)，这是一种基于GD2的抗原，在肿瘤细胞上有限制性表达。用化学酶法合成了9NHAc-GD2，并将其与高效载体噬菌体Qβ偶联。用Q-β−9NHAc-GD2结合物免疫小鼠可产生较强且持久的抗体，对9NHAc-GD2具有很高的选择性，与GD2几乎没有交叉识别。用Qβ−9NHAc-GD2免疫犬，表明该载体对犬具有免疫原性，几乎没有不良反应，为将来临床移植到人类铺平了道路。通过将噬菌体Qβ病毒样颗粒与化学酶合成的模拟9-O-乙酰化GD2抗原的9-NHAC-GD2偶联，制备了一种潜在的抗癌疫苗。这种结合物在小鼠和狗身上产生了强大和持久的免疫球蛋白抗体反应，没有观察到不良反应。
Ganglioside GD2 is an attractive tumor-associated carbohydrate antigen for anti-cancer vaccine development. However, its low immunogenicity and the significant side effects observed with anti-GD2 antibodies present significant obstacles for vaccines. To overcome these, a new GD2 derivative bearing an N-acetamide (NHAc) at its non-reducing end neuraminic acid (9NHAc-GD2) has been designed to mimic the 9-O-acetylated-GD2 (9OAc-GD2), a GD2 based antigen with a restricted expression on tumor cells. 9NHAc-GD2 was synthesized efficiently via a chemoenzymatic method and subsequently conjugated with a powerful carrier bacteriophage Qβ. Mouse immunization with the Qβ−9NHAc-GD2 conjugate elicited strong and long-lasting IgG antibodies, which were highly selective toward 9NHAc-GD2 with little cross-recognition of GD2. Immunization of canines with Qβ−9NHAc-GD2 showed the construct was immunogenic in canines with little adverse effects, paving the way for future clinical translation to humans. A potential anticancer vaccine was produced by the conjugation of bacteriophage Qβ virus-like particle with the chemoenzymatically synthesized 9-NHAc-GD2 mimic of the 9-O-acetylated GD2 antigen. The conjugate produced robust and long-lasting IgG responses in mice and canines with no observed adverse effects.
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