Voici une offre de postdoc au sein de l'équipe IMT de l'UMR7292 du CNRS.
DEVELOPMENT OF NEW ANTIBODY-DRUG CONJUGATES TARGETING BREAST CANCERS
Offer type: post-doctoral fellowship
Financing: Public: Centre-Val de Loire Region (cluster Biomedicines)
Salary range: 1550-2680 € monthly net income, according to the candidate experience
Recruiting organization: UMR7292 GICC CNRS - Université de Tours, Equipe « Innovation Moléculaire et Thérapeutique » (IMT)
Workplace: TOURS - FRANCE
Skill area: therapeutic chemistry, organic chemistry, heterocyclic chemistry
The scientific activity of our UMR, GICC (Genetics, Immunology, Chemistry and Cancer) is based on an interdisciplinary approach ensured by clinicians, biologists and chemists. This UMR includes 38 permanent staff. Our team « Innovation Moléculaire et Thérapeutique » (IMT, 7 permanent staff), directed by Pr. Marie-Claude Viaud-Massuard, is made up of therapeutic and organic chemists, and is part of two Labex (MAbImprove, and SynOrg). The IMT team is specialized in the design and synthesis of small heterocyclic antitumor regulators (e.g. kinases or STAT5 inhibitors). Our expertise in heterocyclic and medicinal chemistry ranges from the development of new organic synthetic methodologies to in silico-assisted lead discovery and optimization. Our team has also an expertise in bioconjugation of small cytotoxic molecules to therapeutic antibodies (mAbs) via a suitably constructed spacer arm (linker) to form antibody-drug conjugates (ADCs). These skills allowed us to design and synthesize new site-specific heterobifunctional linkers permitting access to homogeneous ADCs, from any native antibody (patented methodology). We also developed an analytical physico-chemical platform dedicated to ADC analysis.
Subject of the project:
A grant from the Centre-Val de Loire Region (cluster Biomedicines) is available in our team (IMT). A part of this grant is dedicated to a 1-year post-doctoral fellowship starting as soon as possible, under the supervision of Dr. Nicolas Joubert. This work will focus on the development of original antibody-drug conjugates (ADCs) for the treatment of breast cancers (BC), including triple-negative breast cancer (TNBC).
Breast cancer is the most common cancer in European women. In recent years, the introduction of new anti-HER2 antibody-based treatments such as trastuzumab (Herceptin®) and the ADC trastuzumab-emtansine (T-DM1, Kadcyla®) drastically improved overall survival. However, T-DM1 is known to have a narrow therapeutic window and a very limited action on low HER2 expressing cells. Moreover, despite the favorable efficacy profile of T-DM1 therapy in HER2-positive metastatic or locally advanced, unresectable breast cancer, acquired resistance is commonly observed during a continued treatment. There is consequently an urgent need to circumvent these limitations by developing innovative therapies. One of the different strategies that can be proposed to circumvent the T-DM1 limited efficacy on low HER2 expressing cells is the modification of the payload (cytotoxic agent) mechanism of release inside the tumor. In this project, we will develop original ADCs against several mammary tumors, by using some endogenous stimuli to release the payload selectively inside the tumor. Moreover, we will generate homogeneous ADCs through an in-house patented methodology (actually, using this methodology, from trastuzumab we generated 6 ADCs, including 3 as active as T-DM1, all of them exhibited in vitro an EC50 below 30pM in SK-BR-3 HER2 over-expressing cell line). We already have all the active collaborations needed for this project, including the biologists for the generation of antibodies against tumor and the biological evaluations of our ADCs on tumor models (in vitro and in vivo), as well as a chemical analyst (spectroscopy analyses of ADCs). The candidate will be in charge of the organic synthesis of the linker-payload entities. The applicant will also be responsible for the bioconjugation of the linker-payload entities to the mAb. ADCs characterizations and biological evaluations on vitro and in vivo models will be carried out by different partners of this national interdisciplinary scientific program.
The candidate must have a good knowledge of organic chemistry, and hold a PhD in therapeutic or organic chemistry. An experience in medicinal chemistry will be much appreciated. Knowledge in chemical biology (bioconjugation) will be really appreciated but is not mandatory, as the great challenge of this project will be the design and organic synthesis of the original linkers, and bioconjugation will be taught if necessary. The candidate must very motivated and able to make experiments with great care and reproducibility (needed for bioconjugation). The candidate must also be autonomous, demonstrate a high degree of motivation for working in an interdisciplinary project, and master organic synthesis and analytical techniques (especially HPLC).
Nicolas JOUBERT, MCU
UMR7292 GICC CNRS - Université de Tours
Equipe « Innovation Moléculaire et Thérapeutique »
UFR des Sciences Pharmaceutiques
31 avenue Monge, 37200 Tours
Phone: 33 (0)2 47 36 72 28
Fax: 33 (0)2 47 36 72 29
Keywords: cancer, therapeutic chemistry, organic chemistry, heterocyclic chemistry, bioconjugation, chemical biology.