DEVELOPMENT OF A NEW GENERATION OF ANTIBODY-DRUG CONJUGATES

L’effectif du CEPR inclut des immunologistes, des microbiologistes, des biochimistes spécialistes des protéases et des anti-protéases, des chimoistes organiciens, des experts des aérosols thérapeutiques, des experts en modèles murins et primates de pathologies pulmonaires ainsi que des cliniciens, des pharmaciens, bénéficiant d’une reconnaissance nationale et internationale dans leurs domaines respectifs. Cette diversité est une richesse qui permet le développement d’une recherche à la fois collaborative, translationnelle et productive visant à améliorer les traitements différentes pathologies.

Dans les années à venir, les avancées thérapeutiques proviendront de la découverte de nouvelles cibles et/ou de molécules anti-inflammatoires et anti-infectieuses mais également de l’amélioration des médicaments actuels, via la modification de leur index thérapeutique, de leur pharmacocinétique ou de leur ciblage en modifiant par exemple leur modalité d’administration (e.g. aérosols…). C’est dans ces directions que s’inscrivent aussi les travaux du CEPR. 

Il est important de souligner qu’en France, très rares sont les laboratoires développant une recherche axée à la fois, sur les mécanismes d’inflammation dépendant de la protéolyse ainsi que sur les moyens de les prévenir à l’aide de thérapies ciblées.

DEVELOPMENT OF A NEW GENERATION OF ANTIBODY-DRUG CONJUGATES

Offer type: AI (Assistant Engineer)

Financing Public: C-VALO

Salary range: 1750 € monthly net income (less than 4 years of experience)

Recruiting organization: UMR1100 CEPR, Team 2 “Proteolytic Mechanisms in Inflammation”, group “Immunoconjugates” (C. Denevault, N. Joubert)

Workplace: TOURS - FRANCE

Skill area: bioconjugation, therapeutic chemistry, organic chemistry, heterocyclic chemistry

The scientific activity of our group “Immunoconjugates” (ADCs: antibody-drug conjugates, etc) is based on an interdisciplinary approach ensured by chemists, pharmacists, clinicians and biologists. Our expertise in heterocyclic and medicinal chemistry ranges from the development of new organic synthetic methodologies to the bioconjugation of small cytotoxic molecules onto antibodies (mAbs) via a suitably constructed spacer arm (linker) to form antibody-drug conjugates (ADCs). These skills allowed us to design and synthesize new heterobifunctional linkers permitting access to original homogeneous ADCs, from any native antibody (patented methodologies), with new mechanisms of action, new release mechanisms and/or for new applications.

Subject of the project:

A grant from C-VALO (Centre-Val de Loire Region, FEDER) is available in our group (CEPR, Team 2), as part of the project “ADC4GEN” under the supervision of Dr Caroline Denevault and Dr Nicolas Joubert. This grant is dedicated to a 1-year Assistant Engineer fellowship (Master 2 degree) starting as soon as possible. This work will focus on the development and valorization of proprietary and original antibody-drug conjugates (ADCs) developed in our group.

This grant could eventually be followed by a 3-years PhD grant.

In our group, we recently generated homogeneous ADCs through in-house patented methodologies. Actually, using these methodologies, from trastuzumab (anti-HER2 antibody), we generated several ADCs, some of which exhibited in vitro a subnanomolar activity in SK-BR-3 cell line over-expressing HER2.

TWO PATENTS APPLICATIONS are in progress.

Following this success in oncology, we want to validate our original design for applications in oncology and beyond.

The candidate must have a MASTER 2 degree (BAC+5) and a good knowledge of organic chemistry. Knowledge in chemical biology (bioconjugation) will be really appreciated but is not mandatory (help of a PhD student in our group to learn this expertise). The candidate must be very motivated and able to make experiments with great care and reproducibility (needed for bioconjugation). The candidate must demonstrate a high degree of motivation for working in an interdisciplinary project, and master organic synthesis including purification techniques (flash chromatography and HPLC) and analytical techniques (especially HPLC). In the first months of the program, the candidate will always work in synergy and in company of our PhD student.

For this new project, the recruited Assistant Engineer will be helped and will work in synergy with a third year PhD student to synthesize new linkers for their bioconjugation on different mAbs. The resulted ADCs will then be characterized and evaluated in vitro and in vivo in mouse models.

We have already all the active collaborations needed for this project, including the biologists for the generation of antibodies and the biological evaluations of our ADCs on the particular models of interest (in vitro and in vivo), as well as chemical analysts (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 onto the mAb (know-how will be learned with the PhD student). This program will help set-up new analytical methods. ADCs characterizations and biological evaluations on in vitro and in vivo models will be carried out by different partners of this international interdisciplinary scientific program.