INTERLEUKINS AND THEIR RECEPTORS IN TUMOR BIOLOGY AND AIDS

1)白介素4(IL-4)及其可溶性受体正在检测中 类风湿性关节炎、哮喘和癌症全身注射的临床 或者通过使用病毒载体进行基因转移。目前正在进行研究，以 对其结构、功能、信号转导和靶向进行了研究 IL-4R在免疫细胞和癌细胞上表达。它的结构和功能 另一种与IL-4相关的白细胞介素IL-13的受体也正在 调查过了。重建研究表明，IL-13R a‘ 链，而不是链，是IL-4R系统的一个新成分。它也是 提示IL-4R b链是IL-13R系统的重要组成部分。 因此，IL-4R和IL-13R共享IL-4Rb和IL-13ra‘链。这些研究 有助于解释IL-4和IL-13在许多疾病上的相似生物学活性 不同的细胞类型，包括癌细胞。2)了解 IL-4和IL-13信号转导的分子机制 受体，我们研究了JAK的磷酸化和激活 信号转导转录激活因子(STAT) 胞内蛋白质。我们的研究表明，IL-4和IL-13 可以利用类似的酪氨酸激酶，然而，确实存在一些差异。 IL-13不能磷酸化JAK3酪氨酸激酶。IL-4可以利用 以IL-4Rb链为信号来源的IL-13ra‘或IL-2Rg链 转导。IL-13还利用IL-4Rb和IL-13ra‘链传递信号 转导。这些研究解释了为什么IL-4和IL-13是多余的 对多种细胞类型的影响。额外的重建实验 正在研究哪些激酶与不同的链有关 IL-4和IL-13R复合体。3)IL-4和IL-13R的靶向性 假单胞菌外毒素、白喉毒素或受体 定向基因转移也在研究中。受体的作用 这两种白质细胞因子在人类肿瘤细胞上大量表达。 这为毒素治疗或基因治疗提供了一个有吸引力的靶点。在……里面 利用人脑肿瘤在裸鼠体内的实验证明 100%动物对环状病毒的完全反应 置换的IL-4毒素。包括药代动力学在内的临床前实验 小鼠和毒理学，大鼠脑内给药和 鞘内注射和静脉注射。已经在猴子身上进行了给药。基座 根据这些结果，我们的I期临床试验获得了CBER的批准。我们 曾在圣诞老人约翰·韦恩癌症研究所治疗过11名患者 加利福尼亚州莫尼卡，没有毒性证据。更多的患者正在接受 已在此站点注册，另外七个站点将添加到此站点 学习。这些临床研究将有助于阐明其潜在的安全性。 以及该嵌合毒素和其他嵌合毒素在临床上的有效性 在不同的IND下。

1) Interleukin-4 (IL-4) and its soluble receptor are being tested in the clinic for rheumatoid arthritis, asthma, and cancer by systemic injection or by gene transfer using viral vectors. Studies are underway to characterize structure, function, signal transduction and targeting of IL-4R expressed on immune and cancer cells. The structure and function of receptor for IL-13, another IL-4 related interleukin, is also being investigated. Reconstitution studies have demonstrated that IL-13R a' chain, but not a chain, is a novel component of IL-4R system. It is also demonstared that IL-4R b chain is a neccessary component of IL13R system. Thus, IL-4R and IL-13R share IL4Rb and IL-13Ra' chains. These studies help explain the similar biological activities of IL-4 and IL-13 on many different cell types including cancer cells. 2) To understand the molecular mechanism of signal transduction by the IL-4 and IL-13 receptor, we have studied the phosphorylation and activation of JAK kinases and signal transduction activator of transcription (STAT) intracellular proteins. Our studies demonstrate that both IL-4 and IL-13 can utilize similar tyrosine kinases, however, some differences do exist. IL-13 does not phosphorylate JAK3 tyrosine kinase. IL-4 can utilize either IL-13Ra' or IL-2Rg chain with IL-4Rb chain for its signal transduction. IL-13 also utilizes IL-4Rb and IL-13Ra' chain for signal transduction. These studies explain why IL-4 and IL-13 have redundant effects on a variety of cell types. Additional reconstitution experiments are underway to examine which kinases associate with various chains of IL-4 and IL-13R complexes. 3) The IL-4 and IL-13R directed targeting of a Pseudomonas exotoxin, Diphtheria toxin, or alternatively receptor directed gene transfer is also being investigated. The receptors for these two interleukins are expressed in abundance on human tumor cells that offer an attractive target for toxin therapy or gene therapy. In vivo experiments in nude mice using human brain tumor has demonstrated complete responses in 100% of the animals in response to circular permuted IL-4-toxin. Preclinical experiments including pharmacokinetics and toxicology in mice, intracerebral administration in rats and intrathecal and i.v. administrtaion in monkeys have been performed. Based on these results, our Phase I clinical trial was approved by CBER. We have treated eleven patients at John Wayne Cancer Institute, Santa Monica, CA with no evidence of toxicity. Additional patients are being enrolled at this site and seven additional sites are being added to this study. These clinical studies will help elucidate the potential safety and efficacy of this and other chimeric toxins being tested in clinic under various INDs.