Colitis ImmunoPET: Defining Target Cell Populations and Optimizing Pharmacokinetics
Colitis ImmunoPET: Defining Target Cell Populations and Optimizing Pharmacokinetics
复制标题
DOI：
10.1097/mib.0000000000000677
复制
发表时间：
2016-03-01
影响因子：
4.9
通讯作者：
Packard, Alan B.
中科院分区：
文献类型：
--
作者：
Dearling, Jason L. J.;Daka, Ala;Packard, Alan B.
背景：正电子发射断层扫描结合特异性探头能够无创性评估炎症性肠病。我们先前报道了结肠炎小鼠中Cu-64标记的抗β 7整联蛋白抗体（克隆FIB 504.64）的肠摄取增加。在这里，我们评估了抗α（4）β（7）整联蛋白抗体（克隆DATK 32），以及抗β（7）抗体的F（ab '）（2）和Fab片段，其应具有比完整抗体更快的血液清除，作为用于检测小鼠模型中结肠炎的成像探针。结果：早在注射后1小时，在肠道中就观察到抗β（7）片段的局灶性摄取，并且它们从正常组织中清除的速度比完整抗体更快。例如，注射后24小时的血液浓度对于Cu-64标记的DATK 32为23.3 +/-3.0%ID/g，对于FIB 504.64为12.9 +/-2.1%ID/g，对于FIB 504.64-F（ab '）为4.1 +/-0.4%ID/g（2），64-Fab为0.62 +/-0.2%ID/g（P < 0.0001，方差分析）。结肠炎组和对照组之间大肠中DATK 32的摄取比率（1.38）低于FIB 504.64片段（对于F（ab '）（2）为3.15，对于Fab为1.84）或完整的FIB 504.64（1.78）.结论：与抗β 7免疫蛋白相比，Cu-64标记的抗α 4 β 7抗体（DATK 32）的肠摄取率较低，这表明靶向所有表达β 7的淋巴细胞，而不仅仅是那些表达α（4）β（7）的细胞，是开发炎症性肠病显像剂的更有希望的途径。FIB 504.64-F（ab '）（2）片段在结肠炎和对照组之间表现出最大的差异，因此是开发炎性肠病特异性成像剂的最有希望的先导分子。
Background:Positron emission tomography combined with a specific probe presents the ability to noninvasively assess inflammatory bowel disease. We previously reported increased intestinal uptake of a Cu-64-labeled anti-beta(7) integrin antibody (clone FIB504.64) in colitic mice. Here, we evaluated an anti-alpha(4)beta(7) integrin antibody (clone DATK32), and the F(ab ')(2) and Fab fragments of the anti-beta(7) antibody, which should have faster blood clearance than the intact antibody, as imaging probes for the detection of colitis in a mouse model.Methods:The immunoproteins were labeled with Cu-64, injected into mice with dextran sodium sulphate-induced colitis. Positron emission tomography data were collected between 1 and 48 hours postinjection.Results:Focal uptake of the anti-beta(7) fragments was observed in the gut as early as 1 hour postinjection, and they cleared more rapidly from normal tissues than the whole antibody. For example, the blood concentrations at 24 hours postinjection were 23.3 +/- 3.0% ID/g for Cu-64-labeled DATK32, 12.9 +/- 2.1% ID/g for FIB504.64, 4.1 +/- 0.4% ID/g for FIB504.64-F(ab ')(2), and 0.62 +/- 0.2% ID/g for FIB504.64-Fab (P < 0.0001, analysis of variance). The ratio of uptake of DATK32 between the colitis and control groups in the large intestine (1.38) was lower than for the FIB504.64 fragments (3.15 for F(ab ')(2), 1.84 for Fab) or intact FIB504.64 (1.78).Conclusions:The lower intestinal uptake ratio of the Cu-64-labeled anti-alpha(4)beta(7) antibody (DATK32) compared with the anti-beta(7) immunoproteins suggests that targeting all beta(7)-expressing lymphocytes, not just those expressing alpha(4)beta(7), is a more promising route to the development of an inflammatory bowel disease imaging agent. The FIB504.64-F(ab ')(2) fragment demonstrated the greatest differential between colitis and control groups, and is therefore the most promising lead molecule for the development of an inflammatory bowel disease-specific imaging agent.