GROWTH FACTOR RECEPTOR TARGETED TOXINS FOR LEUKEMIA

本申请书建议设立一个国家 合作药物开发组（NCDDG） RFA 87-CA-25来自美国国家癌症研究所。 的焦点 这个NCDDG将开发一组新的 用于治疗特定白血病的嵌合毒素， 淋巴瘤 这些嵌合毒素是由基因组装而成的 从cDNA或合成基因编码细胞特异性生长 这些因子融合在正确的翻译阅读框架中， 一种截短的白喉毒素结构基因。 我们已经证明 得到的毒素相关/生长因子融合蛋白， 从嵌合毒素基因表达的毒素保留了 免疫决定因素及其生物学功能 零部件 例如， 从白细胞介素-2和白喉毒素的截短形式， 专门针对并只毒害那些 携带T细胞高亲和力受体的真核细胞 生长因子IL-2。 因此，我们使用的细胞特异性 生长因子传递白喉的细胞毒活性 毒素片段A的靶细胞的胞质溶胶。 在这些 例如，靶细胞的胞质溶胶内的延伸因子2是 ADP-核糖基化，并由此抑制蛋白质合成 导致靶细胞死亡。 我们已经证明所有HTLV-I 感染的、转化的人类T细胞系， 亲和力IL-2受体，到目前为止测试，被杀死的皮摩尔 浓度的IL-2毒素;而受体阴性细胞是 对这种嵌合毒素的作用具有抗性。 本 NCDDG将开发IL-2毒素的变体， 长期目标是创造新的生物制剂用于治疗 携带IL-2受体的白血病和淋巴瘤。 我们将 研究嵌合体的结构/功能关系 毒素，其生物学方面的IL-2受体， 正常和恶性细胞，以及它们在体内的生物学。 我们还 应检查高亲和力IL-2的分布和诱导 受体的肿瘤细胞上， 白血病/淋巴瘤。 此外，我们将创建一个新的嵌合体 基于白细胞介素-4的毒素，研究白细胞介素-4-毒素在两者中的作用 体外和体内，并检查IL-4的分布 来自白血病/淋巴瘤患者的细胞上的受体。 是 设想这些研究将导致一类新的高度 用于治疗选定的 白血病和淋巴瘤。

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.