CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory

Tours, France

CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory

Tours, France
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Caldano M.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory
Therapeutic Drug Monitoring | Year: 2017

ABSTRACT: Multiple Sclerosis (MS) is a heterogeneous disease. Although several EMA approved Disease Modifying Treatments including biopharmaceuticals are available, their efficacy is limited and a certain percentage of patients are always non-responsive. Drug Efficacy Monitoring is an important tool to identify these non-responsive patients early on. Currently, Detection of Anti-Drug Antibodies and quantification of Biological Activity are used as methods of efficacy monitoring for Interferon beta (IFNβ) and Natalizumab (NAT) therapies. For NAT and Alemtuzumab treatments, drug level quantification could be an essential component of the overall disease management. Thus, utilization and development of strategies to determine treatment response are vital aspects of MS management given the tremendous clinical and economic promise of this tool. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.


Souffrin A.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | Croix C.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | Viaud-Massuard M.-C.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory
European Journal of Organic Chemistry | Year: 2012

Maleimides are involved for the first time in Sonogashira cross-coupling reactions. Sonogashira conditions have been developed to allow subsequent coupling of various terminal alkynes at room temperature in moderate to excellent yields. These results open the way to innovative synthesis strategies for various difunctionalized maleimide derivatives. The reactivity of maleimides in Sonogashira cross-coupling reactions was studied. The important role of the base is demonstrated, and optimized experimental conditions are described with a large variety of alkynes. The reactivity of the alkynes is also discussed. This reaction provides rapid access to a wide range of new maleimide derivatives in moderate to excellent yields. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Borowiec A.-S.,University of Picardie Jules Verne | Hague F.,University of Picardie Jules Verne | Gouilleux-Gruart V.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | Lassoued K.,University of Picardie Jules Verne | Ouadid-Ahidouch H.,University of Picardie Jules Verne
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2011

Insulin-like Growth Factor-1 (IGF-1) plays a key role in breast cancer development and cell cycle regulation. It has been demonstrated that IGF-1 stimulates cyclin expression, thus regulating the G1 to S phase transition of the cell cycle. Potassium (K+) channels are involved in the G1 phase progression of the cell cycle induced by growth factors. However, mechanisms that allow growth factors to cooperate with K+ channels in order to modulate the G1 phase progression and cyclin expression remain unknown. Here, we focused on hEag1 K+ channels which are over-expressed in breast cancer and are involved in the G1 phase progression of breast cancer cells (MCF-7). As expected, IGF-1 increased cyclin D1 and E expression of MCF-7 cells in a cyclic manner, whereas the increase of CDK4 and 2 levels was sustained. IGF-1 stimulated p21WAF1/Cip1 expression with a kinetic similar to that of cyclin D1, however p27Kip1 expression was insensitive to IGF-1. Interestingly, astemizole, a blocker of hEag1 channels, but not E4031, a blocker of HERG channels, inhibited the expression of both cyclins after 6-8h of co-stimulation with IGF-1. However, astemizole failed to modulate CDK4, CDK2, p21WAF1/Cip1 and p27Kip1 expression. The down-regulation of hEag1 by siRNA provoked a decrease in cyclin expression. This study is the first to demonstrate that K+ channels such as hEag1 are directly involved in the IGF-1-induced up-regulation of cyclin D1 and E expression in MCF-7 cells. By identifying more specifically the temporal position of the arrest site induced by the inhibition of hEag1 channels, we confirmed that hEag1 activity is predominantly upstream of the arrest site induced by serum-deprivation, prior to the up-regulation of both cyclins D1 and E. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. © 2011 Elsevier B.V.


Gaudray P.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory
Medecine Therapeutique Medecine de la Reproduction, Gynecologie et Endocrinologie | Year: 2015

The knowledge that science elaborates of the molecular mechanisms of heredity, of which DNA is a major basis, is a highly dynamic scientific and intellectual object. It is on a very partial understanding that the will, the desire or even the need is grounded to use DNA and to manipulate it in order to remedy health problems (personal as well as public health). This genetic engineering carries great expectations, and as such, leads to promises, the promises of a better future. These expectations are grounded on some idealization of what bio-technique can achieve, and they lead to a blind faith in the power that human achievements may have to improve our condition. This claim leads to a fascination with biotechnology, and to consider only the immediate risks to which a technical answer can be given. Can we stay at this "basic" level of reflection, or should we think further about what this means for the society in which we wish to live, and its long-term future? This approach is that of ethics.


Boucle S.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | Guillard J.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory
Synthesis | Year: 2011

The first synthesis of pyrido[3,2-b]carbazole as an ellipticine- makaluvamine hybrid in 13 steps and 2% overall yield from commercially available 2,5-dimethoxyaniline is described. © Georg Thieme Verlag Stuttgart · New York.


Monoclonal antibodies (MoAb) are very different from other drugs. The Round Table aimed to determine whether the specific characteristics of MoAb have repercussions on their clinical development, evaluation by the health authorities, and long-term monitoring. As regards the structure-activity relationship of MoAb, classification according to mechanism of action (neutralising or agonist MoAb, cytolytic MoAb) is more relevant than to their degree of humanisation. Recommendations on their clinical development would be useful since the early phases give rise to a number of problems and are insufficiently codified. The pharmacokinetic profile is very different from that of other drugs. The concentration-effect relationship is difficult to study since the biomarkers may be apparently disconnected from the therapeutic effect. The methodology for evaluation of MoAb by the agencies, and postmarketing surveillance do not differ from the procedures used for other drugs; however, MoAb bring together a number of specific characteristics as compared with other drugs. © 2012 Société Française de Pharmacologie et de Thérapeutique.


Ternant D.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | Bejan-Angoulvant T.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | Passot C.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | Mulleman D.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | Paintaud G.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory
Clinical Pharmacokinetics | Year: 2015

Monoclonal antibodies (mAbs) are increasingly used to treat rheumatoid arthritis (RA). At present, anti-tumor necrosis factor-α drugs (infliximab, adalimumab, certolizumab pegol, and golimumab), rituximab, and tocilizumab are approved for RA treatment. This review focuses on the pharmacokinetics and pharmacodynamics of mAbs approved in RA. Being large proteins, mAbs exhibit complex pharmacokinetic and pharmacodynamic properties. In particular, owing to the interactions of mAbs with their antigenic targets, the pharmacokinetics of mAbs depends on target turnover and exhibits non-specific (linear) and target-mediated (often nonlinear) clearances. Their volume of distribution is low (3–4 L) and their elimination half-life usually ranges from 2 to 3 weeks. The inter-individual pharmacokinetic variability of mAbs is usually large and is partly explained by differences in antigenic burden or by anti-drug antibodies, which accelerate mAb elimination. The inter-individual variability of clinical response is large and influenced by the pharmacokinetics. The analysis of mAbs concentration-effect relationship relies more and more often on pharmacokinetic-pharmacodynamic modeling; these models being suitable for dosing optimization. Even if adverse effects of mAbs used in RA are well known, the relationship between mAb concentration and adverse effects is poorly documented, especially for anti-tumor necrosis factor-α mAbs. Overall, RA patients treated with mAbs should benefit from individualized dosing strategies. Because of the complexity of their pharmacokinetics and mechanisms of action, the current dosing strategy of mAbs is not based on sound knowledge. New studies are needed to assess individual dosing regimen, adjusted notably to disease activity. © 2015, Springer International Publishing Switzerland.


Tougeron D.,University of Poitiers | Lecomte T.,University of Tours | Lecomte T.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | Pages J.C.,University of Tours | And 7 more authors.
Annals of Oncology | Year: 2013

Background: Only patients with wild-type (WT) KRAS tumors benefit from anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (Mabs) in metastatic colorectal cancer (mCRC). Pyrosequencing is now widely used for the determination of KRAS mutation burden and a conservative cut-off point of 10% has been defined. Up until now, the impact of low-frequency KRAS mutations (<10%) on the response to anti-EGFR Mabs has yet to be evaluated. Patients and methods: Tumors from patients receiving anti-EGFR Mabs based on a WT genotype for KRAS, as determined using direct sequencing, have been retrospectively analyzed by pyrosequencing. Patients were categorized as WT (no KRAS mutation) or low-frequency mutation when KRAS mutation was <10% (KRAS low MT). Results: A total of 168 patients treated by anti-EGFR Mabs for mCRC were analyzed. According to pyrosequencing, 138 tumors remained KRAS WT, while 30 tumors were KRAS low MT. In the KRAS low MT and KRAS WT groups, the response rates were 6.7% and 37.0%, respectively, while stabilization amounted to 23.3% versus 32.6% and progression to 70% versus 29% (P < 0.01). Progression-free survival (PFS) was 2.7 ± 0.5 months for KRAS low MT and was 6.0 ± 0.3 months for KRAS WT (P < 0.01). Conclusions: These results appear to validate consideration of low-frequency KRAS mutation tumors as positive, and justify a large-scale prospective study. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Bire S.,University of Tours | Rouleux-Bonnin F.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory
Topics in Current Genetics | Year: 2013

Integrative gene transfer performed by viral and non-viral vectors have demonstrated their effectiveness, but have been linked to some adverse events, such as clonal expansion and tumorigenesis. These observations have raised serious concerns about the safety of gene transfer methods, and have led to many attempts to find new solutions. In this chapter, we summarize the major problems encountered with viral and non-viral-vectors and various ways of avoiding insertional mutagenesis, the induction of innate immunity and transgene silencing are described. We also list the main strategies for optimizing vector architecture so as to ensure safe and long-term expression of the transgene. Several new approaches have succeeded in targeting transgene integration to a specific locus using recombinases, homing endonucleases, zinc finger nucleases, integrases and transposases or a combination of them. Here, we report various criteria that can be used to define what is a good insertion site in the human genome. © 2013 Springer Science+Business Media B.V.


Guillon-Munos A.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | Daguet A.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | Watier H.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory
mAbs | Year: 2014

The annual "LabEx MAbImprove industrial workshops" are primarily intended to provide scientists involved in therapeutic antibodies, a comprehensive view about topics of interest for the pharmaceutical industry. They are organized by the "LabEx MAbImprove industrial committee", for this first edition especially in partnership with ARITT, the regional agency for innovation and technology transfer which operates in the French Région Centre, the 1st French region for pharmaceutical production. The 2013 edition, held May 28 at the Vinci Center of Tours, was dedicated to antibody biosimilars. Depending on opinions, the impending expiry of antibody patents and the imminent marketing approval of competitors to blockbusters can be perceived as good or bad things. Fears or opportunities? Risks for patients? Breath of fresh air for the health systems? Opportunity for re-industrializing France? In this context, it is necessary for people to form a fair and informed opinion on the current landscape of antibody biosimilars. In particular, this is especially important for scientists from the academic world, from the industry or from the regulation agencies, for pharmacists, for pharmacovigilance specialists, for health authorities, and staff from health insurance and decision makers. The first session was devoted to market and regulatory issues, and included both an overview of the evolution of the patent landscape and a description of biosimilars regulation in the European Union (EU). This session was closed by a talk on manufacturing processes for biosimilars. In the next session, quality control attributes of biosimilars were discussed and compared with the consistent quality of biotechnology products to raise the question: "How close is close enough?" In vitro assays for evaluating the Fc function of therapeutic antibodies were also discussed. The third session focused on development of biosimilars and primarily on the stepwise process for introducing an antibody biosimilar on the EU market, and included a presentation of the ongoing clinical evaluation of an infliximab biosimilar. The session concluded with a rich debate on the indication extrapolation of a biosimilar compared to the originator. The last session was dedicated to societal issues and focused on two aspects: (1) the need of biosimilars for EU health economy; and (2) last but not least, the ethical issues about clinical evaluation of biosimilars. All speakers and attendees enjoyed this very stimulating and rewarding meeting, which gathered many people with divergent scientific backgrounds from the academic or industrial world. © 2014 Landes Bioscience.

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