Isoaspartyl Modified Tumor Antigens for Vaccination

描述（由申请人提供）：本提案将利用几个独特的观察结果来理解调节自身免疫反应发展的自身蛋白的特性。在定义狼疮自身抗原的隐性自身肽的尝试中，我们发现一种特定的自肽翻译后修饰引发了强烈的B细胞和T细胞自身免疫。翻译后肽修饰称为异天冬氨酸，发生在天冬氨酸侧链的羧基（2'）碳与蛋白质内邻近的伯胺基形成环状中间体时。对肿瘤的免疫可以从“自身免疫”的角度来看，因为许多肿瘤抗原是在其他自身组织和细胞上发现的。该建议将尝试利用肿瘤肽免疫的新策略来启动和维持对肿瘤的“自身免疫”反应。

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.