This grant application proposed the establishment of a National Drug Discovery Group (NCDDG) whose focus is on a detailed molecular genetic and biologic analysis of Interleukin-7 (IL-7), the IL-7 receptor (IL-7R), and the IL-7R targeted fusion toxin DAB389IL-7. Interleukin-7 has been shown to stimulate the proliferation and induce signal transduction events in both B and T-cell progenitors, myeloid cells, mature T-cells, and a variety of patient leukemia and lymphoma cells in vitro. The proposed NCDDG is composed of investigators whose expertise ranges from molecular genetics, immunology, transgenic mice, to signal transduction and clinical medicine.
The specific aims of the NCDDG are to develop a detailed understanding of the structure function relationships of IL-7 with particular emphasis on receptor binding and signal transduction leading to the potential discovery of IL-7R antagonists which may be of considerable use in the management of a variety of leukemias/lymphomas. Additional specific aims are focused on the development of a detailed understanding of the biology of the IL-7 / IL-7R system using transgenic mice, as well as the immunotoxicology of Il-7 and related compounds in the modulation of the immune system. We shall also focus our attention on the pre-clinical development of a unique fusion toxin that is composed of the catalytic and transmembrane domains of diphtheria toxin and IL-7 as the receptor binding domain. The design, construction, expression, and purification of this fusion toxin (DAB389IL- 7) have been accomplished. DAB389IL-7 has been shown to be highly toxic for cells that express the IL-7R and will serve as a prototype for clinical development of IL-7R targeted cytotoxic agents. This proposal is modelled after our previous NCDDG award which brought the Il-2R targeted cytotoxin DABV389IL-2 to phase I/II clinical trials. Indeed, this agent has been shown to be safe, well tolerated, and to induce durable complete and partial remissions in those hematologic malignancies which are characterized by the expression of the high affinity IL-2 receptor. It is envisioned that research proposed in this application will be pivotal in bringing IL-7 and/or IL-7 variants, and DAB389Il-7 to clinical trials.
| Cosenza, L; Rosenbach, A; White, J V et al. (2000) Comparative model building of interleukin-7 using interleukin-4 as a template: a structural hypothesis that displays atypical surface chemistry in helix D important for receptor activation. Protein Sci 9:916-26 |
| Rich, B E (1997) Autocrine expression of interleukin-7 rescues lymphoid expansion in interleukin-7-deficient mice. Immunology 92:374-80 |
