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 View Full Text


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Article Info

DATE

2011-09-01

AUTHORS

Caroline Rousseau, Anne Lise Ruellan, Karine Bernardeau, Françoise Kraeber-Bodéré, Sebastien Gouard, Delphine Loussouarn, Catherine Saï-Maurel, Alain Faivre-Chauvet, John Wijdenes, Jacques Barbet, Joëlle Gaschet, Michel Chérel, François Davodeau

ABSTRACT

BackgroundOverexpression 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.MethodThe 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.Results125I-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.ConclusionThese 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. More... »

PAGES

20

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/2191-219x-1-20

DOI

http://dx.doi.org/10.1186/2191-219x-1-20

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1046579495

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/22214534


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13 schema:description BackgroundOverexpression 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.MethodThe 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.Results125I-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.ConclusionThese 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.
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19 schema:keywords B-B4
20 CD138
21 CD138 expression
22 ConclusionThese results
23 MBq
24 MDA-MB-468
25 MDA-MB-468 breast cancer cell line
26 MDA-MB-468 cells
27 MDA-MB-468 xenograft tumors
28 MTD
29 RIT efficacy
30 Scatchard analysis
31 affinity
32 aggressive phenotype
33 analysis
34 antigen
35 biodistribution studies
36 breast cancer
37 breast cancer cell lines
38 breast carcinoma
39 cancer
40 cancer cell lines
41 carcinoma
42 cell lines
43 cells
44 complete response
45 control
46 days
47 diagnosis
48 dose
49 efficacy
50 expression
51 expression of CD138
52 hormone therapy
53 imaging
54 immuno-PET
55 immuno-PET imaging
56 immunohistochemistry
57 immunoreactivity
58 immunotherapy
59 injection
60 interest
61 isotype-matched control
62 lines
63 mAbs
64 maximum
65 metastatic triple-negative breast cancer
66 mice
67 nanomolar range
68 new targets
69 nude mice
70 objective
71 phenotype
72 poor prognosis
73 potential
74 preclinical studies
75 prognosis
76 promising new target
77 quantitative imaging
78 radioimmunotherapy
79 range
80 response
81 results
82 retention
83 single treatment
84 specificity
85 study
86 syndecan-1
87 target
88 therapy
89 treatment
90 triple-negative breast cancer
91 tumor uptake
92 tumor-bearing mice
93 tumors
94 uptake
95 vivo
96 xenograft tumors
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