NOD-5 is a CD4+ T cell clone that we have isolated from the nonobese diabetic (NOD) mouse. This T cell clone and a hybridoma derived from it produce a novel soluble biological activity which induces apoptosis in a variety of tumor cell lines, including B and T lymphoma and leukemia cell lines, transformed fibroblastic cell lines, pancreatic beta-islet tumor and pituitary tumor cell lines. The activity, TAA (tumor apoptotic activity) is protease sensitive and is estimated to be 10-20 kDa by gel filtration and sucrose gradient sedimentation. This activity is distinct from the TNF-alpha/beta, perforin, and Fas mediated apoptosis pathways. Analysis of its activity against a variety of target cell types reveals striking tumor cell specificity in genetically matched fibroblasts. Of particular interest is the ability of TAA to kill p53-deficient tumor cell line. The p53 gene has been implicated as one of the most commonly mutated genes in human cancer. Nearly all human tumors have been shown to harbor p53 mutations. Cell lines containing either p53 mutations or deletions are resistant to radiation induced apoptosis, implicating p53 in mediating death in this setting. Clinical studies have shown that mutations in p53 are correlated with worsened prognosis in many of the most common human malignancies. The ability of TAA to kill p53-=deficient tumor cells holds great promise as a natural nontoxic immunotherapeutic agent for treatment of tumors harboring p53 mutations, which are often resistant to treatment by common antineoplastic therapies. The phase I objective is to purify TAA to homogeneity and to determine the amino acid sequences of tryptic peptides derived form th purified TAA. This will provide the basis for phase II work, which will be to clone the TAA cDNA, to generate active recombinant TAA protein (rTAA), and to test rTAA for efficacy in treatment of malignancies in animal models. PROPOSED COMMERCIAL APPLICATION: TAA is a novel tumor cell specific apoptotic lymphokine secreted by a murine T lymphocyte clone. Of particular value is its ability to kill p53-deficient tumor cells. The novel TAA holds great commercial potential as a natural and nontoxic antineoplastic agent for treatment of malignancies, especially those that harbor mutations of p53, which are associated with poorer prognosis for traditional irradiation and chemotherapy.
Thesaurus Terms:biological response modifier, biotechnology, lymphokine, programmed cell death, protein sequence, tumor suppressor protein helper T lymphocyte, neoplasm /cancer chemotherapy, neoplasm /cancer immunotherapy, tumor suppressor gene clone cell, high performance liquid chromatography, protein purification, recombinant proteinNational Cancer Institute (NCI)
