ImmunoPET Imaging of CTLA-4 Expression in Mouse Models of Non-small Cell Lung Cancer

被引:76
|
作者
Ehlerding, Emily B. [1 ]
England, Christopher G. [1 ]
Majewski, Rebecca L. [2 ]
Valdovinos, Hector F. [1 ]
Jiang, Dawei [3 ]
Liu, Glenn [4 ]
McNeel, Douglas G. [4 ]
Nickles, Robert J. [1 ]
Cai, Weibo [1 ,2 ,3 ]
机构
[1] Univ Wisconsin, Dept Med Phys, Madison, WI 53705 USA
[2] Univ Wisconsin, Dept Biomed Engn, Madison, WI 53705 USA
[3] Univ Wisconsin, Dept Radiol, Madison, WI 53705 USA
[4] Univ Wisconsin, Dept Med, Madison, WI 53705 USA
基金
美国国家卫生研究院;
关键词
CTLA-4 (cytotoxic T-lymphocyte-associated protein 4); immunotherapy; PET (positron emission tomography); lung cancer; immune checkpoint inhibitor; ADVANCED MELANOMA; BLOCKADE; PET; COMBINATION; IPILIMUMAB; THERAPY;
D O I
10.1021/acs.molpharmaceut.7b00056
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is expressed on the surface of activated T cells and some tumor cells, and is the target of the clinically approved monoclonal antibody ipilimumab. In this study, we investigate specific binding of radiolabeled ipilimumab to CTLA-4 expressed by human non-small cell lung cancer cells in vivo using positron emission tomography (PET). Ipilimumab was radiolabeled with Cu-64 (t(1/2) = 12.7 h) through the use of the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to formulate Cu-64-DOTA-ipilimumab. CTLA-4 expression in three non-small cell lung cancer (NSCLC) cell lines (A549, H460, and H358) was verified and quantified by Western blot and enzyme-linked immunosorbent assays (ELISA). A receptor binding assay was utilized to monitor the binding and internalization of Cu-64-DOTA-ipilimumab in the NSCLC cell lines. Next, the biodistribution of Cu-64-DOTA-ipilimumab was mapped by longitudinal PET imaging up to 48 h after injection. Ex vivo biodistribution and histological studies were employed to verify PET results. By in vitro analysis, CTLA-4 was found to be expressed on all three NSCLC cell lines with A549 and H358 showing the highest and lowest level of expression, respectively. PET imaging and quantification verified these findings as the tracer accumulated highest in the A549 tumor model (9.80 +/- 0.22% ID/g at 48 h after injection; n = 4), followed by H460 and H358 tumors with uptakes of 9.37 +/- 0.26%ID/g and 7.43 +/- 0.05% ID/g, respectively (n = 4). The specificity of the tracer was verified by injecting excess ipilimumab in A549 tumor-bearing mice, which decreased tracer uptake to 6.90 +/- 0.51%ID/g at 48 after injection (n = 4). Ex vivo analysis following the last imaging session also corroborated these findings. Cu-64-DOTA-ipilimumab showed enhanced and persistent accumulation in CTLA-4-expressing tissues, which will enable researchers further insight into CTLA-4 targeted therapies in the future.
引用
收藏
页码:1782 / 1789
页数:8
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