Bifunctional T cell receptor based immunotherapeutics

描述（由申请人提供）：这些研究的目标是进一步临床前开发可溶性三域单链t细胞受体IL-2融合蛋白（264scTCR/IL-2）。这种t细胞受体识别人类肿瘤抑制蛋白p53的未突变肽表位，在HLA-A2.1的背景下呈现，在MHC限制性肽特异性结合方面具有完全功能。像264scTCR/IL-2这样的融合蛋白正被开发为癌症治疗的靶向剂，以创造比目前批准的治疗方法疗效更好、毒性和/或副作用更小的产品。与基于全抗体的治疗相比，这些基于tcr的融合蛋白的中等亲和力和较小的分子量应该允许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高水平表达，并且很容易用免疫亲和层析纯化。264scTCR/IL-2融合蛋白在裸鼠中对人类肿瘤具有生物活性，其抗肿瘤活性优于FDA批准的IL-2。这些有希望的结果促使这种融合蛋白继续发展，以用于可能的临床应用。在这些研究中，将产生高产细胞系，并优化蛋白质纯化过程，以预期大规模生产1/11期临床试验。一个具有成本效益和简化的过程对于以合理的成本为临床试验产生足够的材料至关重要。264scTCR/IL-2融合蛋白将在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。对该融合蛋白的作用机制及在高严格裸鼠肿瘤模型中的抗肿瘤效果进行评价。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