This application proposes the establishment of a National Cooperative Drug Development Group (NCDDG) in response to RFA 87-CA-25 from the National Cancer Institute. The focus of this NCDDG will be on the development of a novel group of chimeric toxins for the treatment of specific leukemias and lymphomas. These chimeric toxins are genetically assembled from cDNAs, or synthetic genes encoding cell specific growth factors which are fused in correct translational reading frame to a truncated diphtheria toxin structural gene. We have shown that the resulting toxin-related/growth factor fusion proteins that are expressed from the chimeric toxin genes retain both the immunologic determinants and the biologic function of their component parts. For example, the chimeric toxin assembled from interleukin-2 and a truncated form of diphtheria toxin is specifically targeted towards and intoxicates only those eukaryotic cells which bear high affinity receptors for the T-cell growth factor IL-2. As such, we are using the cell specificity of growth factors to deliver the cytotoxic activity of diphtheria toxin fragment A to the cytosol of target cells. In these instances, elongation factor 2 within th cytosol of target cells is ADP-ribosylated, and the resulting inhibition of protein synthesis causes target cell death. We have shown that all HTLV-I infected, transformed human T-cell lines which bear the high affinity IL-2 receptor, so far tested, are killed by pico molar concentrations of IL-2-toxin; whereas receptor negative cells are resistant to the action of this chimeric toxin. In the present proposal, the NCDDG will develop variants of IL-2-toxin with the long term goal of creating new biologicals for the treatment of IL-2 receptor bearing leukemias and lymphomas. We shall investigate structural/functional relationships of the chimeric toxins, their biology with respect to the IL-2 receptor on both normal and malignant cells, and their biology in vivo. Further, we shall examine the distribution and induction of high affinity IL-2 receptors on neoplastic cells from patients with leukemia/lymphoma. In addition, we shall create a new chimeric toxin based on interleukin-4, study the action of IL-4-toxin both in vitro and in vivo, and examine the distribution of the IL-4 receptor on cells from patients with leukemia / lymphoma. It is envisioned that these studies will result in a new class of highly specific and potent biologicals for the treatment of selected leukemias and lymphomas.
Showing the most recent 10 out of 37 publications
