Chemoenzymatically synthesized multimeric Tn/STn MUC1 glycopeptides elicit cancer-specific anti-MUC1 antibody responses and override tolerance
Chemoenzymatically synthesized multimeric Tn/STn MUC1 glycopeptides elicit cancer-specific anti-MUC1 antibody responses and override tolerance
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DOI：
10.1093/glycob/cwj044
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发表时间：
2006-02-01
期刊：
影响因子：
4.3
通讯作者：
Clausen, H
中科院分区：
文献类型：
--
作者：
Sorensen, AL;Reis, CA;Clausen, H
MUC 1粘蛋白代表了癌症免疫治疗的主要靶抗原，因为它在癌症中大量表达且异常糖基化。通过用肽免疫产生对MUC 1的强体液免疫的尝试通常部分由于耐受性而失败。在这项研究中，我们已经开发了化学酶合成的扩展MUC 1 TR糖肽与癌症相关的O-糖基化使用一组重组人糖基转移酶。将具有不同密度的Tn和STn糖型的MUC 1糖肽与KLH缀合用作免疫原以评价最佳疫苗设计。糖肽与完整的O-聚糖占用（每个重复5个位点）引起了最强的抗体反应与MUC 1在乳腺癌细胞系中表达的Balb/c和MUC1.Tg小鼠。诱导的体液免疫反应显示出对癌细胞的显著特异性，表明糖肽设计有望作为癌症疫苗。所引发的免疫应答针对组合糖肽表位，并且肽序列和糖结构对于抗原都是重要的。产生了具有与引发的免疫应答相似的特异性的MAb（5E 5），并且显示具有相同的显著的癌症特异性。这种抗体可能在诊断和免疫预防措施中有希望。
The MUC1 mucin represents a prime target antigen for cancer immunotherapy because it is abundantly expressed and aberrantly glycosylated in carcinomas. Attempts to generate strong humoral immunity to MUC1 by immunization with peptides have generally failed partly because of tolerance. In this study, we have developed chemoenzymatic synthesis of extended MUC1 TR glycopeptides with cancer-associated O-glycosylation using a panel of recombinant human glycosyltransferases. MUC1 glycopeptides with different densities of Tn and STn glycoforms conjugated to KLH were used as immunogens to evaluate an optimal vaccine design. Glycopeptides with complete O-glycan occupancy (five sites per repeat) elicited the strongest antibody response reacting with MUC1 expressed in breast cancer cell lines in both Balb/c and MUC1.Tg mice. The elicited humoral immune response showed remarkable specificity for cancer cells suggesting that the glycopeptide design holds promise as a cancer vaccine. The elicited immune responses were directed to combined glycopeptide epitopes, and both peptide sequence and carbohydrate structures were important for the antigen. A MAb (5E5) with similar specificity as the elicited immune response was generated and shown to have the same remarkable cancer specificity. This antibody may hold promise in diagnostic and immunopreventive measures.