Comparative evaluation of capsular polysaccharide-specific Igm and IgG antibodies and F(ab')2 and fab fragments as delivery vehicles for Radioimmunotherapy of fungal infection
Comparative evaluation of capsular polysaccharide-specific Igm and IgG antibodies and F(ab')2 and fab fragments as delivery vehicles for Radioimmunotherapy of fungal infection
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DOI：
10.1158/1078-0432.ccr-07-0870
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发表时间：
2007-09-15
影响因子：
11.5
通讯作者：
Casadevall, Arturo
中科院分区：
文献类型：
--
作者：
Dadachova, Ekaterina;Bryan, Ruth A.;Casadevall, Arturo
目的：最近有研究表明，在真菌、细菌和病毒感染的实验模型中，用生物体特异性单抗进行放射免疫治疗可用于治疗感染性疾病。为了确定新型隐球菌(CN)放射免疫治疗的最佳载体，我们对衣壳多糖特异性抗体与F(ab‘)(2)和Fab片段进行了比较评价。实验设计：用Re-188标记18137个IgG1和13171个IgM及其同型对照，通过Scatchard和动力学分析评价它们与24067和H99 CN株的结合。在体外放射免疫治疗期间，使用细胞剂量学算法估计所提供的剂量。结果：118B7Ig G1与13F1Ig M结合效果优于13F1Ig M与24067 Cn的结合(K-a分别为1.7×10(9)和5.4×10(7)m ol/L-1)。1 mU Ci Re-188-18B7(55cGy剂量)对24067和H99 CN细胞有明显的杀伤作用，而1mU Ci Re-188-13F1(2cGy剂量)则无明显杀伤作用。在体内，Re-188-18B7特异性地定位于CN感染的小鼠的肺中，而Re-188-13F1的摄取是非特异性的。与完整的In-111-18B7相比，In-111-F(ab‘)(2)片段在48h时在肺中的摄取率较高，在肝脏中的摄取率较低。结论：对免疫球蛋白Ig G和Ig M以及F(ab’)(2)和Fab片段作为放射免疫治疗隐球菌感染的潜在载体的比较评价强烈表明，与靶抗原的亲和力是体内成功靶向感染的重要前提，体外亲和力测量可以预测候选单抗的体内疗效。
Purpose: The applicability of radioimmunotherapy with organism-specific monoclonal antibodies to treatment of infectious disease in experimental models has been recently shown for fungal, bacterial, and viral infections. To identify the best delivery vehicle for radioimmunotherapy of human pathogenic fungus Cryptococcus neoformans (CN), we have done comparative evaluation of capsular polysaccharide-specific antibodies with IgG1 and IgM isotypes and F(ab')(2) and Fab fragments.Experimental Design: 18137 IgG1 and 13171 IgM and their isotype-matching controls were radiolabeled with Re-188, and their binding to 24067 and H99 CN strains was evaluated by doing Scatchard and kinetics analyses. The doses delivered during in vitro radioimmunotherapy were estimated using a cellular dosimetry algorithm. The biodistribuiion of Re-188-labeled 18137 and 13F1 and of In-111-labeled 18137 and its F(ab')(2) and Fab fragments was done in A/JCr mice systemically infected with 24067 CN strain.Results: 118B7 IgG1 showed superior to 13F1 IgM binding to 24067 CN (K-a = 1.7 x 10(9) mol/L-1 and 5.4 x 10(7) mol/L-1, respectively). Substantial killing of 24067 and H99 CN cells was achieved with 1 mu Ci Re-188-18B7 (55 cGy dose), whereas no killing was observed for 1 mu Ci Re-188-13F1 (2 cGy dose). In vivo Re-188-18B7 localized specifically in the lungs of CN-infected mice, whereas uptake of Re-188-13F1 was nonspecific. In-111-F(ab')(2) fragments showed higher uptake in the lungs and lower in the liver at the 48-h time point in comparison with intact In-111-18B7.Conclusions: Comparative evaluation of IgG and IgM and of F(ab')(2) and Fab fragments as potential delivery vehicles for radioimmunotherapy of cryptococcal infection strongly suggests that affinity for the target antigen is an important prerequisite for successful targeting of infection in vivo and that in vitro affinity measurements may predict the in vivo efficacy of candidate monoclonal antibodies.