Custon Designing Peptides for Cancer Immunotherapy

描述(由申请人提供)：特定的主动免疫疗法是一种 治疗癌症的有吸引力的方法。它的毒性比 化疗并引发免疫监视机制，具有潜在的 提供防止肿瘤复发的保护。这样做的长期目标是 研究目的是开发一种有效的免疫疗法，靶向多种抗原表位 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Cw7)，它将扩大患者群体 利益。显著地靶向多个等位基因，包括一个HLA-C等位基因 减少肿瘤免疫逃逸的机会。 具体地说，我们的目标是设计、发现和生成一个经过修改的 同时含有L和D-氨基酸的HER-2/neu多肽，具有刺激作用 抗HER-2/neu细胞毒性T淋巴细胞(CTL)比野生型更强 人类白细胞抗原A1、A2和Cw7的HER-2/neu表位。多肽将理性地 根据我们以前的研究结果设计的，在某些情况下， 位置。使用我们的新型功能筛选试验，我们还将筛选 受约束的“残基优化”组合多肽文库，包含D- 和L-氨基酸-诱导细胞因子(干扰素-g)释放的肽 抗HER-2/neu CTL。这些多肽将被评估为具有 刺激抗野生型CTL分泌更强的干扰素-γ 类型多肽，比野生型多肽本身。的结合亲和力 它们各自的人类白细胞抗原分子的多肽将被确定和关联 与其生物活性(诱导干扰素-γ)分泌有关。侯选人 将测试多肽产生针对修饰的CTL的能力 HER-2/neu多肽，还能引起交叉反应的CTL，能够 杀伤表达野生型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.