Syndecan-1 antigen, a promising new target for triple-negative breast cancer immuno-PET and radioimmunotherapy. A preclinical study on MDA-MB-468 xenograft tumors.
Syndecan-1 antigen, a promising new target for triple-negative breast cancer immuno-PET and radioimmunotherapy. A preclinical study on MDA-MB-468 xenograft tumors.
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DOI：
10.1186/2191-219x-1-20
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发表时间：
2011-09-01
期刊：
影响因子：
3.2
通讯作者：
Davodeau F
中科院分区：
文献类型：
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作者：
Rousseau C;Ruellan AL;Bernardeau K;Kraeber-Bodéré F;Gouard S;Loussouarn D;Saï-Maurel C;Faivre-Chauvet A;Wijdenes J;Barbet J;Gaschet J;Chérel M;Davodeau F
Syndecan-1 (CD138) 在乳腺癌中的过度表达与不良预后和侵袭性表型相关。本研究的目的是评估在移植了三阴性 MDA-MB-468 乳腺癌细胞系的裸鼠中，使用 124I 或 131I 放射性标记的抗人 syndecan-1 B-B4 mAb，通过免疫 PET 成像和放射免疫疗法 (RIT) 靶向 CD138 的潜力。测定125I-B-B4（80%）的免疫反应性，并通过Scatchard分析在体外测量125I-B-B4的亲和力和CD138在MDA-MB-468上的表达。通过免疫组织化学证实了已建立肿瘤上的 CD138 表达。在注射后 4、24、48、72 和 96 小时对小鼠皮下注射 MDA-MB-468 和 125I-B-B4 进行生物分布研究，并与同种型匹配对照进行比较。使用 124I-B-B4 mAb 通过免疫 PET 成像在体内评估肿瘤对 B-B4 的摄取。通过 131I-B-B4 治疗的小鼠测定最大耐受剂量 (MTD)，并评估 RIT 功效。 125I-B-B4 亲和力在纳摩尔范围内 (Kd = 4.39 ± 1.10 nM)。 MDA-MB-468 细胞上的 CD138 表达相当低（Bmax = 1.19 × 104 ± 9.27 × 102 表位/细胞），但通过免疫组织化学测定，所有细胞体内均表达 CD138。 125I-B-B4 的肿瘤摄取在 24 小时每克 14% 注射剂量 (ID) 时达到峰值，并且高于同种型匹配的对照 mAb（24 小时每克 5% ID）。对荷瘤小鼠使用 124I-B-B4 进行的免疫 PET 证实了 B-B4 摄取的特异性及其在肿瘤内的保留。 MTD 达到 22.2 MBq。所有接受 RIT (n = 8) 作为 MTD 单一治疗的小鼠都经历了部分 (n = 3) 或完全 (n = 5) 反应，其中三只在治疗后 95 天仍保持无肿瘤状态。这些结果表明，131I-B-B4 的 RIT 可考虑用于治疗无法从激素疗法或抗 Her2/neu 免疫疗法中获益的转移性三阴性乳腺癌。使用 124I-B-B4 使表达 CD138 的肿瘤可视化的免疫 PET 增强了该 mAb 在诊断和定量成像方面的应用。
Overexpression of syndecan-1 (CD138) in breast carcinoma correlates with a poor prognosis and an aggressive phenotype. The objective of this study was to evaluate the potential of targeting CD138 by immuno-PET imaging and radioimmunotherapy (RIT) using the antihuman syndecan-1 B-B4 mAb radiolabeled with either 124I or 131I in nude mice engrafted with the triple-negative MDA-MB-468 breast cancer cell line. The immunoreactivity of 125I-B-B4 (80%) was determined, and the affinity of 125I-B-B4 and the expression of CD138 on MDA-MB-468 was measured in vitro by Scatchard analysis. CD138 expression on established tumors was confirmed by immunohistochemistry. A biodistribution study was performed in mice with subcutaneous MDA-MB-468 and 125I-B-B4 at 4, 24, 48, 72, and 96 h after injection and compared with an isotype-matched control. Tumor uptake of B-B4 was evaluated in vivo by immuno-PET imaging using the 124I-B-B4 mAb. The maximum tolerated dose (MTD) was determined from mice treated with 131I-B-B4 and the RIT efficacy evaluated. 125I-B-B4 affinity was in the nanomolar range (Kd = 4.39 ± 1.10 nM). CD138 expression on MDA-MB-468 cells was quite low (Bmax = 1.19 × 104 ± 9.27 × 102 epitopes/cell) but all expressed CD138 in vivo as determined by immunohistochemistry. The tumor uptake of 125I-B-B4 peaked at 14% injected dose (ID) per gram at 24 h and was higher than that of the isotype-matched control mAb (5% ID per gram at 24 h). Immuno-PET performed with 124I-B-B4 on tumor-bearing mice confirmed the specificity of B-B4 uptake and its retention within the tumor. The MTD was reached at 22.2 MBq. All mice treated with RIT (n = 8) as a single treatment at the MTD experienced a partial (n = 3) or complete (n = 5) response, with three of them remaining tumor-free 95 days after treatment. These results demonstrate that RIT with 131I-B-B4 could be considered for the treatment of metastatic triple-negative breast cancer that cannot benefit from hormone therapy or anti-Her2/neu immunotherapy. Immuno-PET for visualizing CD138-expressing tumors with 124I-B-B4 reinforces the interest of this mAb for diagnosis and quantitative imaging.