ImmunoPET Imaging of Endogenous and Transfected Prolactin Receptor Tumor Xenografts.
ImmunoPET Imaging of Endogenous and Transfected Prolactin Receptor Tumor Xenografts.
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DOI：
10.1021/acs.molpharmaceut.7b01133
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发表时间：
2018-06-04
影响因子：
4.9
通讯作者：
Carrasquillo JA
中科院分区：
文献类型：
--
作者：
Cheal SM;Ruan S;Veach DR;Longo VA;Punzalan BJ;Wu J;Fung EK;Kelly MP;Kirshner JR;Giurleo JT;Ehrlich G;Han AQ;Thurston G;Olson WC;Zanzonico PB;Larson SM;Carrasquillo JA
用正电子发射同位素标记的抗体已被用于肿瘤检测，预测哪些患者可能对肿瘤抗原导向治疗有反应，并评估药物干预的药效学作用。催乳素受体（PRLR）在乳腺癌和前列腺癌中过表达，是癌症治疗的新靶点。我们评价了REGN 2878（一种抗PRLR单克隆抗体）作为免疫PET试剂。REGN 2878与去铁胺B结合后用Zr-89标记或用I-131/ I-124标记。通过检查母体REGN 2878、DFO-REGN 2878和碘化REGN 2878的增加量对痕量标记的I-131 REGN 2878摄取的影响，进行了母体REGN 2878、DFO-REGN 2878和碘化REGN 2878的半数最大抑制浓度（IC 50）的体外测定。REGN 1932（一种非PRLR结合抗体）用作对照。在携带具有不同PRLR表达水平的肿瘤异种移植物的小鼠中进行成像和生物分布研究，包括MCF-7、转染的MCF-7/PRLR、PC 3和转染的PC 3/PRLR和T4 D 7v 11细胞系。通过比较Zr-89 REGN 2878和REGN 1932评价肿瘤中摄取的特异性，并在体内竞争中比较了既往注射和未注射2 mg非放射性REGN 2878的肿瘤异种移植物中Zr-89 REGN 2878的摄取。DFO-REGN 2878的竞争结合试验（DFO/抗体比为3.53-5.77）显示IC 50值分别为0.4917和0.7136 nM，而亲本REGN 2878为0.3455 nM，I-124 REGN 2878为0.3343 nM。成像和生物分布研究显示，在189 h的延迟时间内，Zr-89 REGN 2878在PRLR阳性异种移植物中具有良好的靶向性（表示为平均值± 1 SD，注射活性百分比/mL（%IA/mL）74.6 ± 33.8%IA/mL）。相比之下，MCF-7/PRLR肿瘤异种移植物显示对照Zr-89 REGN 1932的低摄取（7.0 ± 2.3%IA/mL）和I-124 REGN 2878的极低摄取和快速清除（1.4 ± 0.6%IA/mL）。Zr-89 REGN 2878在各种PRLR肿瘤异种移植模型中具有优异的抗原特异性靶向作用。我们估计，使用基于图像的动力学建模，PRLR抗原具有非常快速的体内周转半衰期约14分钟从细胞膜。尽管估计的肿瘤PRLR表达数量相对适中，但PRLR表达细胞显示Zr-89 REGN 2878抗体的最终保留，摄取似乎与PRLR表达相关。该试剂有可能用于靶向PRLR的临床试验。
Antibodies labeled with positron-emitting isotopes have been used for tumor detection, predicting which patients may respond to tumor antigen-directed therapy, and assessing pharmacodynamic effects of drug interventions. Prolactin receptor (PRLR) is overexpressed in breast and prostate cancers and is a new target for cancer therapy. We evaluated REGN2878, an anti-PRLR monoclonal antibody, as an immunoPET reagent. REGN2878 was labeled with Zr-89 after conjugation with desferrioxamine B or labeled with I-131/ I-124. In vitro determination of the half-maximal inhibitory concentration (IC50) of parental REGN2878, DFO- REGN2878, and iodinated REGN2878 was performed by examining the effect of the increasing amounts of these on uptake of trace-labeled I-131 REGN2878. REGN1932, a non-PRLR binding antibody, was used as a control. Imaging and biodistribution studies were performed in mice bearing tumor xenografts with various expression levels of PRLR, including MCF-7, transfected MCF-7/PRLR, PC3, and transfected PC3/PRLR and T4D7v11 cell lines. The specificity of uptake in tumors was evaluated by comparing Zr-89 REGN2878 and REGN1932, and in vivo competition compared Zr-89 REGN2878 uptake in tumor xenografts with and without prior injection of 2 mg of nonradioactive REGN2878. The competition binding assay of DFO-REGN2878 at ratios of 3.53–5.77 DFO per antibody showed IC50 values of 0.4917 and 0.7136 nM, respectively, compared to 0.3455 nM for parental REGN2878 and 0.3343 nM for I-124 REGN2878. Imaging and biodistribution studies showed excellent targeting of Zr-89 REGN2878 in PRLR-positive xenografts at delayed times of 189 h (presented as mean ± 1 SD, percent injected activity per mL (%IA/mL) 74.6 ± 33.8%IA/mL). In contrast, MCF-7/PRLR tumor xenografts showed a low uptake (7.0 ± 2.3%IA/mL) of control Zr-89 REGN1932 and a very low uptake and rapid clearance of I-124 REGN2878 (1.4 ± 0.6%IA/mL). Zr-89 REGN2878 has excellent antigen-specific targeting in various PRLR tumor xenograft models. We estimated, using image-based kinetic modeling, that PRLR antigen has a very rapid in vivo turnover half-life of ~14 min from the cell membrane. Despite relatively modest estimated tumor PRLR expression numbers, PRLR-expressing cells have shown final retention of the Zr-89 REGN2878 antibody, with an uptake that appeared to be related to PRLR expression. This reagent has the potential to be used in clinical trials targeting PRLR.
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DOI：
10.2967/jnumed.115.172031
发表时间：
2016-10
期刊：
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
影响因子：
--
作者：
Ulaner GA;Hyman DM;Ross DS;Corben A;Chandarlapaty S;Goldfarb S;McArthur H;Erinjeri JP;Solomon SB;Kolb H;Lyashchenko SK;Lewis JS;Carrasquillo JA
通讯作者：
Carrasquillo JA
影响因子：
3.2
作者：
Fung EK;Cheal SM;Fareedy SB;Punzalan B;Beylergil V;Amir J;Chalasani S;Weber WA;Spratt DE;Veach DR;Bander NH;Larson SM;Zanzonico PB;Osborne JR
通讯作者：
Osborne JR
影响因子：
3
作者：
Faupel-Badger, Jessica M.;Duggan, Maire A.;Figueroa, Jonine D.
通讯作者：
Figueroa, Jonine D.
影响因子：
46.9
作者：
Smith-Jones, PM;Solit, DB;Larson, SM
通讯作者：
Larson, SM
影响因子：
--
作者：
Piazza, Timothy M.;Lu, Juu-Chin;Schuler, Linda A.
通讯作者：
Schuler, Linda A.