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Publications (9)54.06 Total impact

  • Cancer Research 08/2015; 75(15 Supplement):1688-1688. DOI:10.1158/1538-7445.AM2015-1688 · 9.33 Impact Factor
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    ABSTRACT: Coltuximab ravtansine (SAR3419) is an antibody-drug conjugate (ADC) targeting CD19 created by conjugating a derivative of the potent microtubule-acting cytotoxic agent, maytansine, to a version of the anti-CD19 antibody, anti-B4, that was humanized as an IgG1 by variable domain resurfacing. Four different linker-maytansinoid constructs were synthesized (average ~ 3.5 maytansinoids/antibody for each) to evaluate the impact of linker-payload design on the activity of the maytansinoid-ADCs targeting CD19. The ADC comprised of DM4 (N2'-deacetyl-N2'-[4-mercapto-4-methyl-1-oxopentyl]-maytansine) conjugated to antibody via the N-succinimidyl-4-(2-pyridyldithio)butyrate (SPDB) linker was selected for development as SAR3419. A molar ratio for DM4/antibody of between 3 and 5 was selected for the final design of SAR3419. Evaluation of SAR3419 in Ramos tumor xenograft models showed that the minimal effective single dose was about 50 µg/kg conjugated DM4 (~2.5 mg/kg conjugated antibody), while twice this dose gave complete regressions in 100% of the mice. SAR3419 arrests cells in the G2/M phase of the cell cycle, ultimately leading to apoptosis after about 24 h. The results of in vitro and in vivo studies with SAR3419 made with DM4 that was [3H]-labeled at the C20 methoxy group of the maytansinoid suggest a mechanism of internalization and intracellular trafficking of SAR3419, ultimately to lysosomes, in which the antibody is fully degraded, releasing lysine-Nε-SPDB-DM4 as the initial metabolite. Subsequent intracellular reduction of the disulfide bond between linker and DM4 generates the free thiol species which is then converted to S-methyl DM4 by cellular methyl transferase activity. We provide evidence to suggest that generation of S-methyl DM4 in tumor cells may contribute to in vivo tumor eradication via bystander killing of neighboring tumor cells. Furthermore, we show that S-methyl DM4 is converted to the sulfoxide and sulfone derivatives in the liver, suggesting that hepatic catabolism of the payload to less cytotoxic maytansinoid species contributes to the overall therapeutic window of SAR3419. This compound is currently in phase II clinical evaluation for the treatment of diffuse large B cell lymphoma.
    Molecular Pharmaceutics 04/2015; 12(6). DOI:10.1021/acs.molpharmaceut.5b00175 · 4.38 Impact Factor
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    ABSTRACT: Purpose: To develop and compare three copper 64 ((64)Cu)-labeled antibody fragments derived from a CA6-targeting antibody (huDS6) as immuno-positron emission tomography (immuno-PET)-based companion diagnostic agents for an antibody-drug conjugate by using huDS6. Materials and methods: Three antibody fragments derived from huDS6 were produced, purified, conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and evaluated in the following ways: (a) the affinity of the fragments and the DOTA conjugates was measured via flow cytometry, (b) the stability of the labeled fragments was determined ex vivo in human serum over 24 hours, and (c) comparison of the in vivo imaging potential of the fragments was evaluated in mice bearing subcutaneous CA6-positive and CA6-negative xenografts by using serial PET imaging and biodistribution. Isotype controls with antilysozyme and anti-DM4 B-Fabs and blocking experiments with an excess of either B-Fab or huDS6 were used to determine the extent of the antibody fragment (64)Cu-DOTA-B-Fab binding specificity. Immunoreactivity and tracer kinetics were evaluated by using cellular uptake and 48-hour imaging experiments, respectively. Statistical analyses were performed by using t tests, one-way analysis of variance, and Wilcoxon and Mann-Whitney tests. Results: The antibody fragment (64)Cu-DOTA-B-Fab was more than 95% stable after 24 hours in human serum, had an immunoreactivity of more than 70%, and allowed differentiation between CA6-positive and CA6-negative tumors in vivo as early as 6 hours after injection, with a 1.7-fold uptake ratio between tumors. Isotype and blocking studies experiments showed tracer-specific uptake in antigen-positive tumors, despite some nonspecific uptake in both tumor models. Conclusion: Three antibody fragments were produced and examined as potential companion diagnostic agents. (64)Cu-DOTA-B-Fab is a stable and effective immuno-PET tracer for CA6 imaging in vivo.
    Radiology 02/2015; 276(1):140058. DOI:10.1148/radiol.15140058 · 6.87 Impact Factor
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    ABSTRACT: CD38 is a type II transmembrane glycoprotein with both ADP-rybosyl cyclase and glycohydrolase activities. CD38 is highly expressed at the surface of malignant plasma cells of multiple myeloma. SAR650984 is a humanized IgG1 antibody targeting CD38 in early clinical developement that is acting through several potential mechanisms including ADCC, CDC and pro-apoptotic activity. Here we report further preclinical characterization of SAR650984 with a high resolution structure of Fab-SAR650984 in complex with CD38 allowing an epitope mapping. The crystal structure of SAR650984-Fab/huCD38 complex shows that SAR650984 neither blocks the access nor alters the configuration of the ADPRC catalytic site of CD38 although in vitro assays have demonstrated that SAR650984 behaves as a strong inhibitor of the ADPRC activity of CD38. These results suggest that SAR650984 is likely an allosteric antagonist of CD38 that alters the dynamics of enzyme upon binding.
    Acta Crystallographica Section A: Foundations and Advances 08/2014; 70(a1):C1813-C1813. DOI:10.1107/S205327331408187X
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    ABSTRACT: Purpose: The CD38 cell surface antigen is expressed in diverse hematologic malignancies including multiple myeloma, B-cell non-Hodgkin lymphoma (NHL), B-cell chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia (ALL), and T-cell ALL. Here, we assessed the antitumor activity of the anti-CD38 antibody SAR650984. Experimental design: Activity of SAR650984 was examined on lymphoma, leukemia and multiple myeloma cell lines, primary multiple myeloma samples, and multiple myeloma xenograft models in immunodeficient mice. Results: We identified a humanized anti-CD38 antibody with strong proapoptotic activity independent of cross-linking agents, and potent effector functions including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis (ADCP), equivalent in vitro to rituximab in CD20+ and CD38+ models. This unique antibody, termed SAR650984, inhibited the ADP-ribosyl cyclase activity of CD38, likely through an allosteric antagonism as suggested by 3D structure analysis of the complex. In vivo, SAR650984 was active in diverse NHL, ALL, and multiple myeloma CD38+ tumor xenograft models. SAR650984 demonstrated single-agent activity comparable with rituximab or cyclophosphamide in Daudi or SU-DHL-8 lymphoma xenograft models with induction of the proapoptotic marker cleaved capase-7. In addition, SAR650984 had more potent antitumor activity than bortezomib in NCI-H929 and Molp-8 multiple myeloma xenograft studies. Consistent with its mode of action, SAR650984 demonstrated potent proapoptotic activity against CD38+ human primary multiple myeloma cells. Conclusion: These results validate CD38 as a therapeutic target and support the current evaluation of this unique CD38-targeting functional antibody in phase I clinical trials in patients with CD38+ B-cell malignancies.
    Clinical Cancer Research 07/2014; 20(17). DOI:10.1158/1078-0432.CCR-14-0695 · 8.72 Impact Factor

  • Cancer Research 08/2013; 73(8 Supplement):4735-4735. DOI:10.1158/1538-7445.AM2013-4735 · 9.33 Impact Factor
  • Ingrid Sassoon · Véronique Blanc ·
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    ABSTRACT: Biological therapies play an increasing role in cancer treatment, although the number of naked antibodies showing clinical efficacy as single agent remains limited. One way to enhance therapeutic potential of antibodies is to conjugate them to small molecule drugs. This combination is expected to bring together the benefits of highly potent drugs on the one hand and selective binders of specific tumor antigens on the other hand. However, designing an ADC is more complex than a simple meccano game, requiring thoughtful combination of antibody, linker, and drugs in the context of a target and a defined cancer indication. Lessons learned from the first-generation antibody-drug conjugate (ADC) and improvement of the technology guided the design of improved compounds which are now in clinical trials. Brentuximab vedotin (Adcetris(®)), an anti-CD30 antibody conjugated to a potent microtubule inhibitor for the treatment of Hodgkin's lymphoma and anaplastic large cell lymphomas, is the only marketed ADC today. A total of 27 ADC are currently undergoing clinical trials in both hematological malignancies and solid tumor indications. Among them, T-DM1 (trastuzumab emtansine), an ADC comprised of trastuzumab conjugated to DM1, via a non-cleavable linker, is showing very promising results in phase III for the treatment of HER2-positive refractory/relapsed metastatic breast cancer. Other compounds, such as CMC-544, SAR3419, CDX-011, PSMA-ADC, BT-062, and IMGN901 currently in clinical trials, targeting varied antigens and bearing different linker and drugs, contribute to the learning curve of ADC, as do the discontinued ADC. Current challenges include improvement of the therapeutic index, linked to a careful selection of the targets, a better understanding of ADC mechanism of action, the management and understanding of ADC off-target toxicities, as well as the selection of appropriate clinical settings (patient selection, dosing regimen) where these molecules can bring highest clinical benefit.
    Methods in molecular biology (Clifton, N.J.) 08/2013; 1045:1-27. DOI:10.1007/978-1-62703-541-5_1 · 1.29 Impact Factor

  • European Journal of Cancer 11/2012; 48:99. DOI:10.1016/S0959-8049(12)72123-8 · 5.42 Impact Factor
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    ABSTRACT: SAR3419 is a novel anti-CD19 humanized monoclonal antibody conjugated to a maytansine derivate through a cleavable linker for the treatment of B-cell malignancies. SAR3419 combines the strengths of a high-potency tubulin inhibitor and the exquisite B-cell selectivity of an anti-CD19 antibody. The internalization and processing of SAR3419, following its binding at the surface of CD19-positive human lymphoma cell lines and xenograft models, release active metabolites that trigger cell-cycle arrest and apoptosis, leading to cell death and tumor regression. SAR3419 has also been shown to be active in different lymphoma xenograft models, including aggressive diffuse large B-cell lymphoma, resulting in complete regressions and tumor-free survival. In these models, the activity of SAR3419 compared favorably with rituximab and lymphoma standard of care chemotherapy. Two phase I trials with 2 different schedules of SAR3419 as a single agent were conducted in refractory/relapsed B-cell non-Hodgkin lymphoma. Activity was reported in both schedules, in heavily pretreated patients of both follicular and diffuse large B-cell lymphoma subtypes, with a notable lack of significant hematological toxicity, validating SAR3419 as an effective antibody-drug conjugate and opening opportunities in the future. Numerous B-cell-specific anti-CD19 biologics are available to treat B-cell non-Hodgkin lymphoma, and early phase I results obtained with SAR3419 suggest that it is a promising candidate for further development in this disease. In addition, thanks to the broad expression of CD19, SAR3419 may provide treatment options for B-cell leukemias that are often CD20-negative.
    Clinical Cancer Research 10/2011; 17(20):6448-58. DOI:10.1158/1078-0432.CCR-11-0485 · 8.72 Impact Factor