IN VIVO ACTIVITY OF ANTIGP41 IMMUNOTOXINS

本项目的目标是测试抗艾滋病毒的体内功效 免疫毒素（ITs）。 去糖基化蓖麻毒素A链（dRAC）已被广泛应用于 与抗HIV单克隆抗体偶联， HIV感染细胞 针对gp 4l的抗体的活性是 通过可溶性CD 4增强30至100倍，因此在CD 4存在下， 这些IT在培养系统中显示出大约10，000倍的选择性 一种嵌合IT，其含有附着于 假单胞菌外毒素A（CD 4-PE 40）在体外显示类似的活性， 临床试验失败 在拟议中要检验的假设 针对gp 4l的实验性IT毒性较小， 比CD 4-PE 40更好的药代动力学特性。 这一假设将 在使用辐射NOD/LtSz-scid小鼠的模型中进行测试， NK细胞和补体活性的缺陷，以及scid 突变 这些动物被植入人类淋巴瘤细胞 持续感染分子克隆的HIV NL 3 -4。 在文化中， 超过99%的这些细胞感染了艾滋病毒;当 注射到受辐射的NOD/LtSz-scid小鼠中， 并持续将可检测到的p24抗原释放到血液中 并显示出大量的感染性病毒在脾细胞中， 动物 具体目的是测试抗HIV IT的功效 使用该小鼠模型并研究候选药物的药代动力学 在同一个模型中。

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.