Antibody recognition of a unique tumor-specific glycopeptide antigen
Antibody recognition of a unique tumor-specific glycopeptide antigen
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DOI：
10.1073/pnas.0915176107
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发表时间：
2010-06-01
影响因子：
11.1
通讯作者：
Evans, Stephen V.
中科院分区：
文献类型：
--
作者：
Brooks, Cory L.;Schietinger, Andrea;Evans, Stephen V.
异常糖基化和某些碳水化合物部分的过度表达是癌症的一致特征，并且肿瘤相关寡糖作为免疫治疗的靶点正在被积极研究。糖基化模式中最常见的畸变之一是在苏氨酸或丝氨酸残基上呈现单个 O-连接的 N-乙酰半乳糖胺，称为“Tn 抗原”。尽管 Tn 抗原在癌症中普遍存在，使其自然成为疫苗研究的焦点，但此类碳水化合物部分并不总是具有肿瘤特异性，并且已在胚胎和非恶性成人组织中观察到。在这里，我们报告了单克隆抗体 (237mAb) 复合物与含有 Tn 抗原的真正肿瘤特异性糖肽结合的结构基础。与与简单肽复合的糖肽特异性抗体相比，237mAb 不能识别肽中通过糖取代诱导的构象表位。相反，237mAb 使用由种系基因编码的口袋来完全包裹碳水化合物部分本身，同时与浅槽中的肽部分相互作用。因此，237mAb 通过与肽和抗原聚糖部分的多种弱但特异性相互作用的组合，实现了其惊人的肿瘤特异性，没有观察到与未糖基化肽或游离聚糖的生理交叉反应性。
Aberrant glycosylation and the overexpression of certain carbohydrate moieties is a consistent feature of cancers, and tumor-associated oligosaccharides are actively investigated as targets for immunotherapy. One of the most common aberrations in glycosylation patterns is the presentation of a single O-linked N-acetylgalactosamine on a threonine or serine residue known as the "Tn antigen." Whereas the ubiquitous nature of Tn antigens on cancers has made them a natural focus of vaccine research, such carbohydrate moieties are not always tumor-specific and have been observed on embryonic and nonmalignant adult tissue. Here we report the structural basis of binding of a complex of a monoclonal antibody (237mAb) with a truly tumor-specific glycopeptide containing the Tn antigen. In contrast to glycopeptide-specific antibodies in complex with simple peptides, 237mAb does not recognize a conformational epitope induced in the peptide by sugar substitution. Instead, 237mAb uses a pocket coded by germ-line genes to completely envelope the carbohydrate moiety itself while interacting with the peptide moiety in a shallow groove. Thus, 237mAb achieves its striking tumor specificity, with no observed physiological cross-reactivity to the unglycosylated peptide or the free glycan, by a combination of multiple weak but specific interactions to both the peptide and to the glycan portions of the antigen.