Bifunctional T cell receptor based immunotherapeutics

描述(由申请人提供)：这项研究的总体目标是证明使用双功能T细胞受体(TCR)为基础的免疫疗法用于癌症治疗的原理。这些高亲和力的TCR将被用于靶向肿瘤的免疫调节蛋白，如细胞因子，以根除恶性细胞。这些融合蛋白的TCR部分是在人类白细胞抗原A2的背景下出现的未突变的p53多肽的特异性。已经构建了四种这样的基于TCR的融合蛋白来将IL-2、干扰素-γ、GM-CSF或IgG1运送到恶性肿瘤细胞。TCR/IL-2和TCR/lgG1融合蛋白对MHC限制性多肽的特异性结合和体外生物活性进行了充分的研究。TCR/干扰素-γ和TCR/GM-CSF融合蛋白将具有类似的MHC限制性多肽结合和生物活性。每种融合蛋白在Balb/C小鼠体内的表观血清半衰期和最大耐受量将被确定。最后，这些TCR融合蛋白的抗肿瘤和抗转移活性将在植入人类肿瘤细胞的SCLD小鼠模型系统中进行评估。这些研究的成功完成应有助于开发用于商业化的TCR试剂。

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.