Bifunctional T cell receptor based immunotherapeutics

描述（由申请人提供）：这些研究的目的是进一步临床前开发可溶性三结构域单链T细胞受体IL-2融合蛋白（264 scTCR/IL-2）。这种识别在HLA-A2.1背景下呈递的人肿瘤抑制蛋白p53的未突变肽表位的T细胞受体对于MHC限制性肽特异性结合具有完全功能。像264 scTCR/IL-2这样的融合蛋白正在被开发作为癌症治疗的靶向剂，以努力创造比目前批准的治疗具有更好疗效和更少毒性和/或副作用的产品。这些基于TCR的融合蛋白的中等亲和力和较小分子量应允许比基于全抗体的治疗更好的扩散和肿瘤穿透。这些基于三结构域TCR的融合蛋白在哺乳动物细胞中以高水平表达，并且容易使用免疫亲和层析纯化。发现264 scTCR/IL-2融合蛋白对裸鼠中的人肿瘤具有生物活性，其抗肿瘤活性上级FDA批准的IL-2。这些有希望的结果促使继续开发这种融合蛋白用于可能的临床用途。对于这些研究，将生成高产细胞系，并优化蛋白纯化工艺，以预期用于I/II期临床试验的大规模生产。一个具有成本效益和精简的过程是以合理的成本为临床试验产生足够的材料的关键。264 scTCR/IL-2融合蛋白将在必要的临床前研究中进行评估，以使产品进入1/11期临床试验。这些研究将包括药代动力学、毒性和组织交叉反应性研究。将对该融合蛋白的作用机制进行评价，并评价其在高度严格的裸鼠肿瘤模型中的抗肿瘤功效。这些研究的积极结果将促进该分子继续进入GMP生产和1/11期临床试验

DESCRIPTION (provided by applicant): The goal of these studies is to further pre-clinical development of a soluble three-domain single chain T-cell receptor IL-2 fusion protein (264scTCR/IL-2). This T-cell receptor, which recognizes an unmutated peptide epitope of the human tumor suppressor protein, p53, presented in the context of HLA-A2.1 is fully functional with respect to MHC restricted peptide specific binding. Fusion proteins like 264scTCR/IL-2 are being developed as a targeting agent for cancer therapeutics in an effort to create products with better efficacy and less toxicity and/or side effects than currently approved treatments. The moderate affinities and smaller molecular weights of these TCR-based fusion proteins should allow for better diffusion and tumor penetration than treatments based on full antibodies. These three-domain TCR-based fusion proteins are expressed at high levels in mammalian cells and are readily purified using immunoaffinity chromatography. The 264scTCR/IL-2 fusion protein was found to be biologically active against human tumors in nude mice with anti-tumor activities that are superior to that of the FDA approved IL-2. These promising results have prompted continued development of this fusion protein for possible clinical use. For these studies a high producing cell line will be generated and the protein purification process will be optimized in anticipation of large scale manufacture for phase 1/11clinical trials. A cost effective and streamlined process is critical for generating enough material for clinical trials at a reasonable cost. The 264scTCR/IL-2 fusion protein will be evaluated in pre-clinical studies necessary to move the product forward into phase 1/11clinical trials. These studies will include pharmacokinetics, toxicity, and tissue cross-reactivity studies. The mechanism of action and evaluate the anti-tumor efficacy in highly stringent tumor models in nude mice will be evaluated for this fusion protein. Positive results from these studies will facilitate continued movement of this molecule forwarding to GMP manufacturing and phase 1/11clinical trials