Synthesis of QS-21-xylose: Establishment of the immunopotentiating activity of synthetic QS-21 adjuvant with a melanoma vaccine
Synthesis of QS-21-xylose: Establishment of the immunopotentiating activity of synthetic QS-21 adjuvant with a melanoma vaccine
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DOI：
10.1002/anie.200801885
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发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Gin, David Y.
中科院分区：
文献类型：
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作者：
Deng, Kai;Adams, Michelle M.;Gin, David Y.
抗肿瘤和抗病毒疫苗的成功通常需要使用佐剂，佐剂本身不一定是免疫原性的，但显著增强患者对联合用药抗原的免疫反应。[1]最近许多抗癌免疫治疗进展中的首选佐剂，[2]人类免疫缺陷病毒[3，4]和疟疾[5，6]是天然产物皂苷QS-21。[7]结合癌症疫苗开发的广泛研究表明，在临床前模型中，QS-21优于18种竞争佐剂。[8]从Quillaja Saponaria(QS)树的皮质中微量分离，QS-21不是均相物质；相反，它是半纯化QS-树皮提取物的早期反相(RP)高效液相色谱22个组分中的第21个组分。[7，9]这种佐剂活性组分至少包括两个主要成分(方案1)，QS-21-XYL(1)和QS-21-Api(2)，这两个组分在线性四糖片段中的末端糖残基不同。[10，11]尽管多组分QS-21组分已经推动了许多先前和正在进行的疫苗临床试验，但从自然来源获得成分一致的样品的挑战是巨大的。事实上，即使在类似树龄和当地环境(如土壤、季节)的QS树中也可以看到皂素成分的高度变异性。[12]此外，最近对半纯化的QS树皮提取物进行的代谢组学分析揭示了超过100种不同的皂苷的复杂混合物，[13]比最初的22个组分的RP-HPL C图谱所暗示的要多得多。[7，9]由于QS提取物的变异性和异质性，很难确定其成分皂苷的佐剂活性和毒性。QS-21组分中可能存在微量额外的皂苷，这不仅影响到疗效和配方方面，而且还影响到人类临床疫苗开发的调节障碍。
The success of antitumor and antiviral vaccines often requires the use of an adjuvant, a substance that is itself not necessarily immunogenic but significantly enhances the immune response of a patient to a coadministered antigen.[1] The adjuvant of choice in many recent immunotherapeutic advances against cancer,[2] human immunodeficiency virus,[3, 4] and malaria [5, 6] is the natural product saponin QS-21.[7] Extensive studies in the development of conjugate cancer vaccines demonstrated the superiority of QS-21 over 18 competing adjuvants in preclinical models.[8] Isolated in minute quantities from the cortex of the Quillaja saponaria (QS) tree, QS-21 is not a homogeneous substance; rather, it is the 21st of 22 fractions in an early reversed-phase (RP) HPLC trace of semipurified QS-bark extracts.[7, 9] This adjuvant-active fraction comprises at least two principal constituents (Scheme 1), QS-21-Xyl (1) and QS-21-Api (2), which differ in the terminal sugar residue within the linear tetrasaccharide segment.[10, 11] Although the multicomponent QS-21 fraction has fueled numerous previous and ongoing vaccine clinical trials, the challenge to procure samples of consistent composition from natural sources is formidable. Indeed, high variability in saponin composition is seen even among QS trees of similar age and local environment (eg, soil, season).[12] Furthermore, recent metabolomic analyses of semipurified QS-bark extracts revealed a complex mixture of over 100 distinct saponins,[13] considerably more than what the original 22-fraction RP HPLC profile might imply.[7, 9] Because of the variability and heterogeneity of QS extracts, it is difficult to establish the adjuvant activity and toxicity of the component saponins. The possibility that trace quantities of additional saponins may be present in the QS-21 fraction impacts not only on efficacy and formulation aspects, but also on regulatory hurdles in clinical vaccine development in humans.