Pre-clinical evaluation of immunoPET imaging using agonist CD40 monoclonal antibody in pancreatic tumor-bearing mice.
Pre-clinical evaluation of immunoPET imaging using agonist CD40 monoclonal antibody in pancreatic tumor-bearing mice.
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DOI：
10.1016/j.nucmedbio.2021.04.001
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发表时间：
2021-07
影响因子：
3.1
通讯作者：
Ferrara KW
中科院分区：
文献类型：
--
作者：
Aghevlian S;Wu B;Raie MN;Tumbale SK;Kare AJ;Seo JW;Ferrara KW
研制了一种新型的[64Cu]Cu-NOTA-aCD40免疫pet示踪剂，用于C57BL/6小鼠CD40+胰腺肿瘤模型的成像，并研究了激动剂CD40 （aCD40）单克隆抗体（mAb）单独或与其他单克隆抗体联合的生物分布谱。将铜-64 （[64Cu]Cu）标记的NOTA-aCD40和NOTA-IgG （10 μg; 7 MBq）静脉注射到皮下mT4肿瘤的C57BL/6小鼠体内，通过正电子发射断层扫描/计算机断层扫描（PET/CT）成像和生物分布研究（n = 5）评估注射后48 h的特异性。[64Cu]Cu-NOTA-aCD40单独或同时与冷aCD40 （100 μg）、aPD-1 （200 μg）和aCTLA-4 （200 μg）单克隆抗体联合注射。一组有肿瘤或无肿瘤的小鼠分别间隔1周或3周接受第二轮注射。在每小时48 h进行PET/CT成像和生物分布研究。根据2 μg [64Cu]Cu- nota - acd40（相当于5 mg患者剂量）在非荷瘤小鼠中的生物分布研究估计[64Cu]Cu的器官剂量。[64Cu]Cu-NOTA-aCD40在肿瘤和脾脏中的积累量分别比[64Cu]Cu-NOTA-IgG高2.3倍和7.8倍，表明aCD40单抗在小鼠胰腺肿瘤模型中的特异性。注射后48 h， [64Cu]Cu-NOTA-aCD40的肿瘤蓄积量为21.2±7.3% ID/g。[64Cu]Cu-NOTA-aCD40与单独冷aCD40单抗或与PD-1和CTLA-4单抗共注射可减少脾脏和肿瘤的摄取，而增加肝脏的摄取。在第二轮注射中，肝脏是唯一有大量吸收的器官。剂量学研究中，[64Cu]Cu-NOTA-aCD40给药2 μg时，肝脾比大于10 μg（分别为2.8 vs 0.37）。人体最高剂量器官（肝脏）的当量为198±28.7 μSv/MBq。研制了cd40免疫反应性[64Cu]Cu-NOTA-aCD40探针。脾脏与肝脏积聚的比例超过IgG同型，且在单个小的注射肿块中最大。[64Cu]Cu对人体成像的安全性是基于器官特异性的外推。
A novel [64Cu]Cu-NOTA-aCD40 immunoPET tracer was developed to image a CD40+ pancreatic tumor model in C57BL/6 mice and to study the biodistribution profile of the agonist CD40 (aCD40) monoclonal antibody (mAb) alone or combined with other mAbs. Copper-64 ([64Cu]Cu) labeled NOTA-aCD40 and NOTA-IgG (10 μg; 7 MBq) were injected intravenously into C57BL/6 mice with subcutaneous mT4 tumors to assess specificity 48 h post injection (p.i.) through positron emission tomography/computed tomography (PET/CT) imaging and biodistribution studies (n = 5). [64Cu]Cu-NOTA-aCD40 was injected alone or simultaneously in combination with a therapeutic mass of cold aCD40 (100 μg), aPD-1 (200 μg) and aCTLA-4 (200 μg) mAbs. A group of mice with or without tumor received the second round of injections 1 or 3 weeks apart, respectively. PET/CT imaging and biodistribution studies were performed at 48 h p.i. The organ dose for [64Cu]Cu was estimated based on biodistribution studies with 2 μg [64Cu]Cu-NOTA-aCD40 (corresponds to 5 mg patient dose) in non-tumor bearing mice. [64Cu]Cu-NOTA-aCD40 accumulation was 2.3- and 7.8-fold higher than [64Cu]Cu-NOTA-IgG in tumors and spleen, respectively, indicating the specificity of aCD40 mAb in a mouse pancreatic tumor model. Tumor accumulation of [64Cu]Cu-NOTA-aCD40 was 21.2 ± 7.3 %ID/g at 48 h after injection. Co-injection of [64Cu]Cu-NOTA-aCD40 with cold aCD40 mAb alone or with PD-1 and CTLA-4 mAbs reduced both spleen and tumor uptake, whereas liver uptake was increased. With the second round of injections, the liver was the only organ with substantial uptake. With a 2 μg administered dose of [64Cu]Cu-NOTA-aCD40 in a dosimetry study, the liver to spleen ratio was greater compared to the 10 μg dose (2.8 vs 0.37; respectively). The human equivalent for the highest dose organ (liver) was 198 ± 28.7 μSv/MBq. A CD40-immunoreactive [64Cu]Cu-NOTA-aCD40 probe was developed. The ratio of spleen to liver accumulation exceeded that of the IgG isotype and was greatest with a single small, injected mass. The safety of human patient imaging with [64Cu]Cu was established based on extrapolation of the organ specificity to human imaging.
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影响因子：
3.1
作者：
De Silva, Ravindra A.;Jain, Sandeep;Rogers, Buck E.
通讯作者：
Rogers, Buck E.
影响因子：
4.9
作者：
Aghevlian, Sadaf;Cai, Zhongli;Reilly, Raymond M.
通讯作者：
Reilly, Raymond M.
影响因子：
5.6
作者：
Caisova, Veronika;Uher, Ondrej;Zenka, Jan
通讯作者：
Zenka, Jan
影响因子：
11.5
作者：
Eriksson, Emma;Milenova, Ioanna;Loskog, Angelica
通讯作者：
Loskog, Angelica
影响因子：
64.8
作者：
Herbst RS;Soria JC;Kowanetz M;Fine GD;Hamid O;Gordon MS;Sosman JA;McDermott DF;Powderly JD;Gettinger SN;Kohrt HE;Horn L;Lawrence DP;Rost S;Leabman M;Xiao Y;Mokatrin A;Koeppen H;Hegde PS;Mellman I;Chen DS;Hodi FS
通讯作者：
Hodi FS