Centre de Recherche en Cancérologie de Nantes-Angers, Université de Nantes, Inserm, U892, Nantes, France.
EJNMMI Res. 2011 Sep 1;1(1):20. doi: 10.1186/2191-219X-1-20.
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.
在乳腺癌中， syndecan-1（CD138）的过度表达与预后不良和侵袭性表型相关。本研究的目的是评估通过免疫 PET 成像和放射性免疫治疗（RIT）靶向 CD138 的潜力，使用抗人 syndecan-1 B-B4 mAb 标记 124I 或 131I，在裸鼠中移植三阴性 MDA-MB-468 乳腺癌细胞系。
确定 125I-B-B4 的免疫反应性，并通过 Scatchard 分析测量 125I-B-B4 的亲和力和 MDA-MB-468 上 CD138 的表达。通过免疫组织化学证实建立的肿瘤中 CD138 的表达。在注射后 4、24、48、72 和 96 小时，在皮下 MDA-MB-468 和 125I-B-B4 的小鼠中进行生物分布研究，并与同型对照进行比较。使用 124I-B-B4 mAb 通过免疫 PET 成像评估 B-B4 的体内摄取。从接受 131I-B-B4 治疗的小鼠中确定最大耐受剂量（MTD），并评估 RIT 疗效。
125I-B-B4 亲和力处于纳摩尔范围（Kd = 4.39 ± 1.10 nM）。MDA-MB-468 细胞上的 CD138 表达水平较低（Bmax = 1.19×104±9.27×102 个表位/细胞），但在体内通过免疫组织化学均表达 CD138。125I-B-B4 的肿瘤摄取在 24 小时时达到 14%注射剂量（ID）/克，高于同型对照 mAb（24 小时时 5% ID/克）。在荷瘤小鼠上进行的 124I-B-B4 免疫 PET 证实了 B-B4 摄取的特异性及其在肿瘤内的保留。MTD 在 22.2 MBq 时达到。在 MTD 下接受单次 RIT（n = 8）治疗的所有小鼠均经历部分（n = 3）或完全（n = 5）反应，其中 3 只在治疗后 95 天仍无肿瘤。
这些结果表明，131I-B-B4 的 RIT 可考虑用于治疗不能从激素治疗或抗 Her2/neu 免疫治疗中获益的转移性三阴性乳腺癌。使用 124I-B-B4 进行免疫 PET 以可视化表达 CD138 的肿瘤，进一步证实了该 mAb 用于诊断和定量成像的价值。
