In vitro and in vivo characterization of 64Cu-labeled Abegrin™ a humanized monoclonal antibody against integrin αvβ3
In vitro and in vivo characterization of 64Cu-labeled Abegrin™ a humanized monoclonal antibody against integrin αvβ3
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DOI：
10.1158/0008-5472.can-06-1480
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发表时间：
2006-10-01
期刊：
影响因子：
11.2
通讯作者：
Chen, Xiaoyuan
中科院分区：
文献类型：
--
作者：
Cai, Weibo;Wu, Yun;Chen, Xiaoyuan
Abegrin(TM)(Medi-522或Vitaxin(TM))是一种人源化的抗人整合素α(V)β(3)的单抗，目前正在进行癌症治疗的临床试验。为了更好地进行治疗监测和剂量优化，需要使用基于Abegrin(TM)的探测器进行活体成像。在这里，我们将Abegrin(TM)与大环络合剂1，4，7，10-四氮杂环十二烷N，N‘，N’‘，N’‘-四乙酸酯(DOTA)以五种不同的DOTA/Abegrin(TM)比例偶联。用(CU)-C-标记，半衰期为12.7h，并在三种人(U87 MG、MDAMB-435和PC-3)和一种小鼠(GL-26)肿瘤模型上进行了实验。评价了这些铜--DOTA-阿贝吉林(TM)结合物的体内外效应。每个Abegrin(TM)的DOTA数目在1.65+/-0.32到38.53+/-5.71之间变化，放射性标记率从5.20+/-3.16%到88.12+/-6.98%(以每50亩DOTA-Abegrin(TM)结合物2MCI(CU)-C-为基础)。这些结合物的放射免疫反应性无显著差异(59.78+/-1.33%和71.13+/-2.58%)。微电子发射断层扫描研究表明，铜--DOTA-Abegrin(TM)(1,000：1)对U87 MG肿瘤具有最高的肿瘤活性积聚(71h后注射剂量/g为49.41+/-4.54%)。通过有效阻断肿瘤摄取，证实了铜--DOTA-Abegrin的受体特异性。铜--DOTA-Ig G在检测的所有时间点均显示出本底水平的肿瘤摄取。使用铜--DOTA-Abegrin(TM)的整合素α(V)β(3)特异性肿瘤成像可能被转化到临床，以表征Abegrin(TM)和/或Abegrin结合物的药代动力学、肿瘤靶向效力、剂量优化和剂量间隔。使用Abegrin(TM)作为载体的化疗药物或放射治疗药物在治疗整合素α(V)β(3)阳性肿瘤方面也可能有效。
Abegrin (TM) (MEDI-522 or Vitaxin (TM)), a humanized monoclonal antibody against human integrin alpha(v)beta(3) is in clinical trials for cancer therapy. In vivo imaging using Abegrin (TM)-based probes is needed for better treatment monitoring and dose optimization. Here, we conjugated Abegrin (TM) with macrocyclic chelating agent 1,4,7,10-tetra-azacylododecane N,N',N'',N''-tetraacetic (DOTA) at five different DOTA/Abegrin (TM) ratios. The conjugates were labeled with (CU)-C-64 (half-life = 12.7 hours) and tested in three human (U87MG, MDA-MB-435, and PC-3) and one mouse (GL-26) tumor models. The in vitro and in vivo effects of these Cu-64-DOTA-Abegirin (TM) conjugates were evaluated. The number of DOTA per Abegrin (TM) varied from 1.65 +/- 0.32 to 38.53 +/- 5.71 and the radiolabeling yield varied from 5.20 +/- 3.16% to 88.12 +/- 6.98% (based on 2 mCi (CU)-C-64 per 50 mu g DOTA-Abegrin (TM) conjugate). No significant difference in radioimmunoreactivity was found among these conjugates (between 59.78 +/- 1.33 % and 71.13 +/- 2.58 %). Micro-positron emission tomography studies revealed that Cu-64-DOTA-Abegrin (TM) (1,000:1) had the highest tumor activity accumulation (49.41 +/- 4.54% injected dose/g at 71-hour postinjection for U87MG tumor). The receptor specificity of Cu-64-DOTA-Abegrin was confirmed by effective blocking of MDA-MB-435 tumor uptake with coadministration of nonradioactive Abegrin. Cu-64-DOTA-IgG exhibited background level tumor uptake at all time points examined. Integrin alpha(v)beta(3)-specific tumor imaging using Cu-64-DOTA-Abegrin (TM) may be translated into the clinic to characterize the pharmacokinetics, tumor targeting efficacy, dose optimization, and dose interval of Abegrin (TM) and/or Abegrin conjugates. Chemotherapeutics or radiotherapeutics using Abegrin (TM) as the delivering vehicle may also be effective in treating integrin alpha(v)beta(3)-positive tumors.