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 ? ?
| Fishman, Mayer N; Thompson, John A; Pennock, Gregory K et al. (2011) Phase I trial of ALT-801, an interleukin-2/T-cell receptor fusion protein targeting p53 (aa264-272)/HLA-A*0201 complex, in patients with advanced malignancies. Clin Cancer Res 17:7765-75 |
| Wen, Jinghai; Zhu, Xiaoyun; Liu, Bai et al. (2008) Targeting activity of a TCR/IL-2 fusion protein against established tumors. Cancer Immunol Immunother 57:1781-94 |
| Belmont, Heather J; Price-Schiavi, Shari; Liu, Bai et al. (2006) Potent antitumor activity of a tumor-specific soluble TCR/IL-2 fusion protein. Clin Immunol 121:29-39 |
