Bifunctional T cell receptor based immunotherapeutics

描述（由申请人提供）：本研究的总体目标是证明使用基于双功能T细胞受体（TCR）的免疫治疗药物治疗癌症的原理证明。 这些高亲和力TCR将用于将免疫调节蛋白如细胞因子靶向肿瘤以根除恶性细胞。 这些融合蛋白的TCR部分对HLA-A2背景下呈递的未突变的p53肽是特异性的。 已经构建了四种这样的基于TCR的融合蛋白以将IL-2、IFN-γ、GM-CSF或IgG 1递送至恶性细胞。 TCR/IL-2和TCR/IgG 1融合蛋白已在体外充分表征了MHC限制性肽特异性结合和生物活性。 TCR/IFN-γ和TCR/GM-CSF融合蛋白将类似地表征MHC限制性肽特异性结合和生物活性。 将在Balb/C小鼠中测定每种融合蛋白的表观血清半衰期和最高耐受剂量。 最后，将在使用植入人肿瘤细胞的SClD小鼠的模型系统中评估这些TCR融合蛋白的抗肿瘤和抗转移活性。这些研究的成功完成将促进基于TCR的试剂的商业化开发。

DESCRIPTION (provided by applicant): The overall goal of this research is to demonstrate proof-of-principle for using bifunctional T-cell receptor (TCR)-based immunotherapeutics for the treatment of cancer. These high affinity TCRs will be used to target immunomodulatory proteins such as cytokines to tumors to eradicate malignant cells. The TCR portions of these fusion proteins are specfic for unmutated p53 peptides presented in the context of HLA-A2. Four such TCR-based fusion proteins have been constructed to deliver IL-2, IFN-gamma, GM-CSF, or IgG1 to malignant cells. The TCR/IL-2 and TCR/lgG1 fusion proteins have been fully characterized for MHC restricted peptide specific binding and bioactivity in vitro. The TCR/IFN-gamma and TCR/GM-CSF fusion proteins will be similarly characterized for MHC restricted peptide specific binding and bioactivity. The apparent serum half life and highest tolerated dose will be determined in Balb/C mice for each fusion protein. Finally, the anti-neoplastic and anti-metastatic activity of these TCR fusion proteins will be assessed in a model system using SClD mice implanted with human tumor cells. Successful completion of these studies should facilitate the development of TCR-based reagents for commercialization.