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

International audienceBackgroundOverexpression 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.Results 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.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

Synthesis of precursors for 211At-labelling of anti-PSMA HuJ591 mAb and stability comparison after in vitro cellular internalization

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Long-Term Toxicity of [213]Bi-Labelled BSA in Mice

International audienceBackgroundShort-term toxicological evaluations of alpha-radioimmunotherapy have been reported in preclinical assays, particularly using bismuth-213 ([213]Bi). Toxicity is greatly influenced not only by the pharmacokinetics and binding specificity of the vector but also by non-specific irradiation due to the circulating radiopharmaceutical in the blood. To assess this, an acute and chronic toxicity study was carried out in mice injected with [213]Bi-labelled Bovine Serum Albumin ([213]Bi-BSA) as an example of a long-term circulating vector.MethodBiodistribution of [213]Bi-BSA and [125]I-BSA were compared in order to evaluate [213]Bi uptake by healthy organs. The doses to organs for injected [213]Bi-BSA were calculated. Groups of nude mice were injected with 3.7, 7.4 and 11.1 MBq of [213]Bi-BSA and monitored for 385 days. Plasma parameters, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN) and creatinine, were measured and blood cell counts (white blood cells, platelets and red blood cells) were performed. Mouse organs were examined histologically at different time points.ResultsHaematological toxicity was transient and non-limiting for all evaluated injected activities. At the highest injected activity (11.1 MBq), mice died from liver and kidney failure (median survival of 189 days). This liver toxicity was identified by an increase in both ALT and AST and by histological examination. Mice injected with 7.4 MBq of [213]Bi-BSA (median survival of 324 days) had an increase in plasma BUN and creatinine due to impaired kidney function, confirmed by histological examination. Injection of 3.7 MBq of [213]Bi-BSA was safe, with no plasma enzyme modifications or histological abnormalities.ConclusionHaematological toxicity was not limiting in this study. Liver failure was observed at the highest injected activity (11.1 MBq), consistent with liver damage observed in human clinical trials. Intermediate injected activity (7.4 MBq) should be used with caution because of the risk of long-term toxicity to kidneys

Sensitivity of pretargeted immunoPET using 68 Ga-peptide to detect colonic carcinoma liver metastases in a murine xenograft model: Comparison with 18 FDG PET-CT

International audienceABSTRACT Purpose: The aim of this study was to compare the performances pretargeted immunoPET 68 Ga-PETimaging (68 Ga-pPET) with anti carcino-embryonic antigen (CEA) and anti-histamine-succinyl-glycine (HSG) recombinant humanized bispecific monoclonal antibody (TF2) and 68 Ga-labeled HSG peptide (IMP288) to conventional 18 FDG-PET in an orthotopic murine model of liver metastases of human colonic cancer. Methods: Hepatic tumor burden following intra-portal injection of luciferase-transfected LS174T cells in nude mice was confirmed using bioluminescence. One group of animals was injected intravenously with TF2 and with 68 Ga-IMP288 24 hours later (n=8). Another group received 18 FDG (n=8), and a third had both imaging modalities (n=7). PET acquisitions started 1 hour after injection of the radioconjugate. Biodistributions in tumors and normal tissues were assessed one hour after imaging. Results: Tumor/organ ratios were significantly higher with 68 Ga-pPET compared to 18 FDG-PET (P<0.05) with both imaging and biodistribution data. 68 Ga-pPET sensitivity for tumor detection was 67% vs. 31% with 18 FDG PET (P=0.049). For tumors less than 200 mg, the sensitivity was 44% with 68 Ga-pPET vs. 0% for 18 FDG PET (P=0.031). A strong correlation was demonstrated between tumor uptakes measured on PET images and biodistribution analyses (r 2 =0.85). Conclusion: 68 Ga-pPET was more sensitive than 18 FDG-PET for the detection of human colonic liver metastases in an orthotopic murine xenograft model. Improved tumor/organ ratios support the use of pretargeting method for imaging and therapy of CEA-expressing tumors

Optimization of Dosimetry in Alpha Therapy : Microlocalisation of 223Ra in Mouse Models of Metastasis from Prostate Cancer and Renal Cell Carcinoma

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Optimization of Dosimetry in Alpha Therapy : Microlocalisation of 223Ra in Mouse Models of Metastasis from Prostate Cancer and Renal Cell Carcinoma

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