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

Background: 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 immunoPET imaging and radioimmunotherapy (RIT) using the antihuman syndecan-1 B-B4 mAb radiolabeled with either I-124 or I-131 in nude mice engrafted with the triple-negative MDA-MB-468 breast cancer cell line. Method: The immunoreactivity of I-125-B-B4 (80%) was determined, and the affinity of I-125-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 I-125-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 I-124-B-B4 mAb. The maximum tolerated dose (MTD) was determined from mice treated with I-131-B-B4 and the RIT efficacy evaluated. Results: I-125-B-B4 affinity was in the nanomolar range (Kd = 4.39 x 1.10 nM). CD138 expression on MDA-MB-468 cells was quite low (Bmax = 1.19 x 10(4) x 9.27 x 10(2) epitopes/cell) but all expressed CD138 in vivo as determined by immunohistochemistry. The tumor uptake of I-125-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 I-124-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. Conclusion: These results demonstrate that RIT with I-131-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 I-124-B-B4 reinforces the interest of this mAb for diagnosis and quantitative imaging.