IN VIVO ACTIVITY OF ANTIGP41 IMMUNOTOXINS

该项目的目标是测试体内抗艾滋病毒的效果。 免疫毒素(ITS)。脱脂糖基化蓖麻毒素A链(DRAC) 与抗HIV单抗偶联以构建其杀伤力 感染艾滋病毒的细胞。针对gp4l的抗体的活性是 由可溶的CD_4增强30到100倍，因此在CD_4的存在下 这些ITS在培养系统中显示出大约10,000倍的选择性 一种含有CD4的嵌合IT，附着在有毒部分 假单胞菌外毒素A(CD4-PE40)在体外表现出类似的活性，但 临床试验失败。将在建议的 研究表明，针对gp4l的实验性ITS毒性较低，并具有 比CD4-PE40具有更好的药代动力学特性。这一假说将 在一个模型中使用受辐射的NOD/LtSz-SCID小鼠进行测试，这些小鼠有 NK细胞和补体活性缺陷，以及SCID 突变。这些动物被植入了人类淋巴瘤细胞 持续感染分子克隆艾滋病毒NL3-4。在文化上， 这些细胞中有99%以上感染了艾滋病毒； 注射到受照射的NOD/LtSz-SCID小鼠体内，这些细胞建立肿瘤 并持续将可检测到的p24抗原释放到血液中 并在脾细胞中显示出大量的传染性病毒 动物。具体目的是测试抗HIV ITS的有效性。 利用该小鼠模型研究候选药物的药代动力学 都是同一型号的。

The goal of this project is to test the in vivo efficacy of anti-HIV immunotoxins (ITs). Degylcosylated ricin A-chain (dRAC) has been coupled to monoclonal anti-HIV antibodies to construct ITs that kill HIV-infected cells. The activity of antibodies directed toward gp4l is enhanced 30 to 100-fold by soluble CD4, so that in the presence of CD4 these ITs show approximately 10,000-fold selectivity in culture systems A chimeric IT containing CD4 attached to the toxic portion of pseudomonas exotoxin A (CD4-PE40) shows similar activity in vitro but failed clinical trials. The hypothesis to be tested in the proposed studies is that experimental ITs aimed at gp4l are less toxic and have better pharmacokinetic properties than CD4-PE40. This hypothesis will be tested in a model using irradiated NOD/LtSz-scid mice, which have defects in NK cells and complement activity, as well as the scid mutation. The animals are implanted with human lymphoma cells persistantly infected with molecularly cloned HIV NL3-4. In culture, greater than 99 percent of these cells are infected with HIV; when injected into irradiated NOD/LtSz-scid mice, the cells establish tumors in various sites and persistantly shed detectable p24 antigen into blood and show high numbers of infectious viruses in spleen cells from the animals. The specific aims are to test the efficacy of anti-HIV ITs using this mouse model and to study the pharmacokinetics of candidate ITs in the same model.