Custon Designing Peptides for Cancer Immunotherapy

描述（由申请人提供）：特异性主动免疫疗法是一种 有吸引力的方法来治疗癌症。它的毒性比 化疗和增强免疫监视机制， 从而防止肿瘤复发。长期目标是 该研究旨在开发一种有效的免疫疗法，靶向多个表位， 肿瘤相关抗原Her-2/neu。我们的策略采用了多等位基因 方法（HLA-A1，A2和Cw 7），扩大患者人群， 效益靶向多个等位基因，包括HLA-C等位基因， 减少了肿瘤免疫逃逸的机会 具体来说，我们的目标是设计，发现和生成一个面板的修改 含有L和D-氨基酸的Her-2/neu肽，能够刺激 抗Her-2/neu细胞毒性T淋巴细胞（CTL）比野生型更强 HLA-A1、A2和Cw 7的Her-2/neu肽表位。肽将被合理地 设计基于我们以前的发现，优选的，在某些残基 职位。使用我们新的功能性筛选试验，我们还将筛选 限制的、“残基优化的”含有D- 和诱导细胞因子（IFN-g）释放的肽的L-氨基酸。 抗Her-2/neu CTL。将评价这些肽的能力， 刺激从抗野生型CTL产生更强的γ-干扰素分泌 与野生型肽相比，的结合亲和力 将确定它们各自HLA分子的肽并将其关联 其生物活性（IFN-γ的诱导）分泌。候选 将测试肽产生对修饰的多肽特异性的CTL的能力。 Her-2/neu肽，但也能够引发交叉反应性CTL，能够 杀死表达野生型Her-2/neu的肿瘤。在未来的研究中，我们打算 将这种多等位基因方法扩展到包括其他肿瘤相关抗原。

DESCRIPTION (PROVIDED BY APPLICANT): Specific, active immunotherapy is an attractive approach for the treatment of cancer. It is less toxic than chemotherapy and elicits immune surveillance mechanisms with the potential of providing protection from tumor recurrence. The long-term objective of this study is to develop an effective immunotherapy, targeting multiple epitopes of the tumor associated antigen, Her-2/neu. Our strategy employs a multi-allelic approach (HLA-A1, A2, and Cw7), expanding the patient population it will benefit. Targeting multiple alleles, including an HLA-C allele, significantly decreases the chances of immune escape by the tumor. Specifically, we aim to design, discover and generate a panel of modified Her-2/neu peptides containing both L and D-amino acids, capable of stimulating anti-Her-2/neu cytotoxic T lymphocytes (CTL) more strongly than wild type Her-2/neu peptide epitopes for HLA-A1, A2 and Cw7. Peptides will be rationally designed based upon our previous findings of preferred, residues at certain postitions. Using our novel, functional screening assay, we will also screen constrained, "residue-optimized" combinatorial peptide libraries containing D- and L-amino acids for peptides that induce cytokine (IFN-g) release from anti-Her-2/neu CTL. These peptides will be evaluated for the ability to stimulate stronger interferon-gamma secretion from CTL generated against wild type peptides, than the wild type peptide itself. Binding affinities of the peptides for their respective HLA molecules will be determined and correlated with their biological activities (induction of IFN-gamma) secretion. Candidate peptides will be tested for the ability to generate CTL specific for modified Her-2/neu peptides, but also able to elicit cross-reactive CTL, capable of killing tumors expressing wild type Her-2/neu. In future studies, we intend to expand this multi-allelic approach to include other tumor associated antigens.