Rational Design of Peptide-Based Tumor Vaccine

描述（由申请方提供）：使用与肿瘤相关抗原（TAA）衍生的T细胞反应性片段相对应的合成肽进行疫苗接种，可增强表达相同抗原的患者的抗肿瘤免疫力。越来越多的人认识到，与病毒来源的表位相反，TAA表位通常与MHC分子弱结合，因此不能在体内引发强烈的T细胞应答。改善MHC结合作为上调抗原识别的策略对于癌症的免疫干预具有明确的意义。在过去的二十年中，在结构水平上对MHC/肽相互作用的理解的进展使得基于共同的构象特征识别新的结合基序成为可能。 A2分子的分析表明，水填充的MHC/肽结合界面。这些研究的直接含义是，结合肽的中心部分中的亲水性氨基酸可以间接地与MHC分子相互作用，并且可以调节与T细胞受体的相互作用。提出了具有两个目的的实验计划：（i）研究MAGE-A4表位GVYDGREHTV中的两个中心残基之间的成对相互作用对TCR V β CDR 3使用的多样性。(ii)导出并应用在18种X射线结构中看到的共同结构特征来设计衍生自Melan-A/MART-1、Her-2/neu、MUC 1、CEA、法师-3和AFP的表位。 作为这里提出的研究的结果，我们期望鉴定出适合作为肿瘤免疫治疗中的疫苗候选物的新型肽序列。本申请中提出的研究是重要的，因为在成功完成后，它将提供用于将低亲和力TAA表位转化为高亲和力变体的新标准，所述高亲和力变体可以在体内募集额外的抗原特异性CTL。通过定义MHC/肽/TCR相互作用的复杂性的额外水平，免疫原性肽的更准确的预测将是可能的。这项研究也将有利于开发基于肽的病毒和微生物感染疫苗。

DESCRIPTION (provided by applicant): Vaccination with synthetic peptides corresponding to T-cell reactive fragments derived from tumor associated antigens (TAAs) can bolster anti-tumor immunity in patients expressing the same antigen. It has been increasingly acknowledged that TAA epitopes, in contrast to epitopes of viral origin, generally bind weakly to the MHC molecule and are therefore unable to elicit robust T cell response in vivo. Improving MHC binding as a strategy to upregulate antigen recognition has clear implications for immune intervention of cancer. Advances in the understanding of MHC/peptide interactions at the structural level over the past two decades have allowed the possibility of identifying novel binding motifs based on common conformational features. Analyses of the A2 molecule suggest a water-filled MHC/peptide binding interface. A direct implication of these studies is that hydrophilic amino acids in the central part of the bound peptide can indirectly interact with the MHC molecule and may modulate interactions with the T cell receptor. An Experimental Plan with two aims is proposed to: (i) study the pairwise interaction between two central residues in the MAGE-A4 epitope GVYDGREHTV on the diversity of TCR Vbeta CDR3 usage. (ii) derive and apply a common structural feature seen in eighteen x-ray structures to design of epitopes derived from Melan-A/MART-1, Her-2/neu, MUC1, CEA, MAGE-3, and AFP. As an outcome of the research proposed here, we expect to identify novel peptide sequences that are suitable as vaccine candidates in tumor immunotherapy. The research proposed in this application is significant, because upon successful completion, it will provide new criteria for converting low affinity TAA epitopes into high affinity variants that may recruit additional antigen-specific CTLs in vivo. By defining additional levels of sophistication of MHC/peptide/TCR interactions, more accurate predictions of immunogenic peptides will be possible. The research proposed will also benefit the development of peptide-based vaccines for viral and microbial infections.