GROWTH FACTOR RECEPTOR TARGETED TOXINS FOR LEUKEMIA

本申请建议设立一个国家 合作药物开发小组(NCDDG)回应 来自国家癌症研究所的RFA 87-CA-25。的关注点 这个NCDDG将开发一组新的 嵌合毒素用于治疗特定白血病和 淋巴瘤。这些嵌合毒素是通过基因组装而成的 来自cDNA，或编码细胞特异性生长的合成基因 在正确的翻译阅读框架中融合的因素 截短的白喉毒素结构基因。我们已经证明了 由此产生的毒素相关/生长因子融合蛋白是 表达的嵌合毒素基因既保留了 免疫决定因素及其生物学功能 部件。例如，嵌合毒素组装在一起 来自白介素2和白喉毒素的截短型 专门针对并陶醉于那些 携带高亲和力T细胞受体的真核细胞 生长因子IL-2。因此，我们使用的是细胞特异性 传递白喉细胞毒活性的生长因子 毒素片段A对靶细胞胞浆的作用。在这些 例如，靶细胞胞浆内的伸长因子2是 ADP-核糖化，以及由此导致的蛋白质合成抑制 导致目标细胞死亡。我们已经证明，所有HTLV-I 感染、转化的人类T细胞株，这些T细胞株携带高水平的 目前检测到的亲和力IL-2受体被微摩尔杀死 IL-2毒素浓度；而受体阴性细胞 抵抗这种嵌合毒素的作用。在现在 提议，NCDDG将开发IL-2毒素的变体 创造新的生物制剂治疗糖尿病的长期目标 携带白血病和淋巴瘤的IL-2受体。我们会 研究嵌合体的结构/功能关系 毒素及其与IL-2受体相关的生物学特性 正常细胞和恶性细胞及其在体内的生物学。此外，我们 应检测高亲和力IL-2的分布和诱导 非霍奇金淋巴瘤患者肿瘤细胞上的受体 白血病/淋巴瘤。此外，我们将创建一个新的嵌合体 基于IL-4的毒素，研究IL-4-毒素在大鼠体内的作用 体外和体内，并检测IL-4的分布 白血病/淋巴瘤患者细胞上的受体。它是 预计这些研究将产生一个新的高度 特定有效的生物制剂用于治疗选定的 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.