Improvement of Radioimmunotherapy Using Pretargeting

During the past two decades, considerable research has been devoted to radionuclide therapy using radiolabeled monoclonal antibodies and receptor binding agents. Conventional radioimmunotherapy (RIT) is now an established and important tool in the treatment of hematologic malignancies such as Non-Hodgkin lymphoma. For solid malignancies, the efficacy of RIT has not been as successful due to lower radiosensitivity, difficult penetration of the antibody into the tumor, and potential excessive radiation to normal tissues. Innovative approaches have been developed in order to enhance tumor absorbed dose while limiting toxicity to overcome the different limitations due to the tumor and host characteristics. Pretargeting techniques (pRIT) are a promising approach that consists of decoupling the delivery of a tumor monoclonal antibody (mAb) from the delivery of the radionuclide. This results in a much higher tumor-to-normal tissue ratio and is favorable for therapy as well and imaging. This includes various strategies based on avidin/streptavidin-biotin, DNA-complementary DNA, and bispecific antibody-hapten bindings. pRIT continuously evolves with the investigation of new molecular constructs and the development of radiochemistry. Pharmacokinetics improve dosimetry depending on the radionuclides used (alpha, beta, and Auger emitters) with prediction of tumor response and host toxicities. New constructs such as the Dock and Lock technology allow production of a variety of mABs directed against tumor-associated antigens. Survival benefit has already been shown in medullary thyroid carcinoma. Improvement in delivery of radioactivity to tumors with these pretargeting procedures associated with reduced hematologic toxicity will become the next generation of RIT. The following review addresses actual technical and clinical considerations and future development of pRIT

Comparison of 123 I-metaiodobenzylguanidine (MIBG) and 131 I-MIBG semi-quantitative scores in predicting survival in patients with stage 4 neuroblastoma: A report from the Children's Oncology Group

Background 123 I-metaiodobenzylguanidine (MIBG) scans are preferable to 131 I-MIBG for neuroblastoma imaging as they deliver less patient radiation yet have greater sensitivity in disease detection. Both 123 I-MIBG and 131 I-MIBG scans were used for disease assessments of neuroblastoma patients enrolled on Children's Oncology Group (COG) high-risk study A3973. The hypothesis was that 123 I-MIBG and 131 I-MIBG scans were sufficiently similar for clinical purposes in terms of ability to predict survival. Procedure Patients enrolled on COG A3973 with stage 4 disease who completed 123 I-MIBG or 131 I-MIBG scans at diagnosis, post-induction, post-transplant, or post-biotherapy were analyzed. The performance of the Curie score for each MIBG scan type in predicting survival was evaluated. At each time point, survival curves for 123 I-MIBG versus 131 I-MIBG were compared using the log-rank test. Results Of the 413 patients on A3973 with at least one MIBG scan, 350 were stage 4. The 5-year event-free survival (EFS) and overall survival (OS) rates were 33.4 ± 3.6% and 45.6 ± 4.0% (N = 350). At post-induction, EFS ( P  = 0.3501) and OS ( P  = 0.5337) for 123 I-MIBG versus 131 I-MIBG were not significantly different. Similarly, comparisons at the three other time points were non-significant. Conclusions We found no evidence of a statistically significant difference in outcome by type of scan. For future survival analyses of MIBG Curie scores, 123 I-MIBG and 131 I-MIBG results may be combined and analyzed overall, without adjustment for scan type. Pediatr Blood Cancer 2011;56:1041–1045. © 2011 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83739/1/22991_ftp.pd

Fully human IgG and IgM antibodies directed against the carcinoembryonic antigen (CEA) Gold 4 epitope and designed for radioimmunotherapy (RIT) of colorectal cancers

BACKGROUND: Human monoclonal antibodies (MAbs) are needed for colon cancer radioimmunotherapy (RIT) to allow for repeated injections. Carcinoembryonic antigen (CEA) being the reference antigen for immunotargeting of these tumors, we developed human anti-CEA MAbs. METHODS: XenoMouse(®)-G2 animals were immunized with CEA. Among all the antibodies produced, two of them, VG-IgG2κ and VG-IgM, were selected for characterization in vitro in comparison with the human-mouse chimeric anti-CEA MAb X4 using flow cytometry, surface plasmon resonance, and binding to radiolabeled soluble CEA and in vivo in human colon carcinoma LS174T bearing nude mice. RESULTS: Flow cytometry analysis demonstrated binding of MAbs on CEA-expressing cells without any binding on NCA-expressing human granulocytes. In a competitive binding assay using five reference MAbs, directed against the five Gold CEA epitopes, VG-IgG2κ and VG-IgM were shown to be directed against the Gold 4 epitope. The affinities of purified VG-IgG2κ and VG-IgM were determined to be 0.19 ± 0.06 × 10(8 )M(-1 )and 1.30 ± 0.06 × 10(8 )M(-1), respectively, as compared with 0.61 ± 0.05 × 10(8 )M(-1 )for the reference MAb X4. In a soluble phase assay, the binding capacities of VG-IgG2κ and VG-IgM to soluble CEA were clearly lower than that of the control chimeric MAb X4. A human MAb concentration of about 10(-7 )M was needed to precipitate approximatively 1 ng (125)I-rhCEA as compared with 10(-9 )M for MAb X4, suggesting a preferential binding of the human MAbs to solid phase CEA. In vivo, 24 h post-injection, (125)I-VG-IgG2κ demonstrated a high tumor uptake (25.4 ± 7.3%ID/g), close to that of (131)I-X4 (21.7 ± 7.2%ID/g). At 72 h post-injection, (125)I-VG-IgG2κ was still concentrated in the tumor (28.4 ± 11.0%ID/g) whereas the tumor concentration of (131)I-X4 was significantly reduced (12.5 ± 4.8%ID/g). At no time after injection was there any accumulation of the radiolabeled MAbs in normal tissues. A pertinent analysis of VG-IgM biodistribution was not possible in this mouse model in which IgM displays a very short half-life due to poly-Ig receptor expression in the liver. CONCLUSION: Our human anti-CEA IgG2κ is a promising candidate for radioimmunotherapy in intact form, as F(ab')(2 )fragments, or as a bispecific antibody

La construction des ports de plaisance dans le Morbihan : une alternative au déclin de l’économie locale traditionnelle

Introduction Cette contribution porte sur une étude de la genèse des ports de plaisance, en prenant appui sur l’exemple du département du Morbihan. Celle-ci s’inscrit dans la perspective d’une sociologie empirique de l’action publique et se propose de rendre compte et d’expliciter les situations et les enjeux complexes qui ont conduit le Conseil général – aujourd’hui Conseil départemental – de ce département à créer sa propre société d’aménagement et de gestion des ports de plaisance, la SATM..