Isoaspartyl Modified Tumor Antigens for Vaccination

描述（由申请人提供）：该提案将利用在理解调节自身免疫反应发展的自身蛋白质的特性中所做的几个独特观察。在试图定义狼疮自身抗原的隐蔽自身肽时，我们发现自身肽的特定翻译后修饰引起强烈的B和T细胞自身免疫。当天冬氨酸侧链的羧基（2 '）碳与蛋白质内相邻的伯胺基团形成环状中间体时，发生翻译后肽修饰（称为异戊酰基）。对肿瘤的免疫可以在“自身免疫”的背景下看待，因为许多肿瘤抗原在其他自身组织和细胞上发现。该提案将尝试利用肿瘤肽免疫的新策略来启动并维持对肿瘤的“自身免疫”应答。 自身蛋白的异戊酰基形式具有刺激自身免疫和抗肿瘤免疫的能力，其方式是自身蛋白的“正常”戊酰基形式失效。本建议将利用这些观察结果，试图刺激抗肿瘤B和T细胞免疫。初步研究表明，黑色素瘤蛋白质TRP-2的异戊酰肽在动物模型中刺激抗肿瘤免疫。我们将进一步研究抗肿瘤反应的机制，并利用其他修饰的肿瘤肽在黑色素瘤动物模型中引发抗肿瘤免疫。预计这种方法将导致用于治疗人类肿瘤的新型免疫疗法。

DESCRIPTION (provided by applicant): This proposal will take advantage of several unique observations made in understanding the properties of self proteins that regulate the development of autoimmune responses. In attempts to define cryptic self peptides of lupus autoantigens, we found that a particular post-translational modification of a self peptide elicited strong B and T cell autoimmunity. The post-translational peptide modification, termed isoaspartyl, occurs when the carboxyl (2') carbon of an aspartic acid side chain forms a cyclic intermediate with the neighboring primary amine group within a protein. Immunity to tumors may be viewed in the context of "autoimmunity" since many tumor antigens are found on other self tissues and cells. This proposal will attempt to initiate and perpetuate an "autoimmune" response to tumors utilizing a novel strategy of tumor peptide immunization. Isoaspartyl forms of self proteins have the ability to stimulate both autoimmunity and anti-tumor immunity in a manner where the "normal" aspartyl form of the self protein fails. The present proposal will exploit these observations in attempts to stimulate anti-tumor B and T cell immunity. Preliminary studies indicate that the isoaspartyl peptide of a melanoma protein, TRP-2, stimulates anti-tumor immunity in animal models. We will further examine the mechanisms of the anti-tumor response and utilize other modified tumor peptides to elicit anti-tumor immunity in animal models of melanoma. It is anticipated that this approach will lead to novel immunotherapies for the treatment of human tumors.