Reference : UPR4301-VINAUC-001
Workplace : ORLEANS
Date of publication : Thursday, June 16, 2022
Scientific Responsible name : Vincent AUCAGNE
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 1 October 2022
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly
Description of the thesis topic
title: Design, synthesis and validation of monodomain antibodies as pharmacological tools
The advent of monoclonal antibodies (mAbs) and their conjugates (e.g. Antibody-drug conjugates, ADC) have revolutionized targeted therapies and imaging, particularly in oncology. However, they suffer from yet unresolved drawbacks, such as production and characterization difficulties, leading to heterogeneous bioconjugates in terms of potency and toxicity. Although the “humanization” of mAbs greatly reduces their immunogenicity, they often remain immunogenic in humans. In addition, their bulky size impairs their effectiveness in penetrating tumors. Nanobodies (Nbs) are the smallest fragments of natural antibodies (10 times smaller than a mAb) which retain affinities for the antigen comparable to mAbs. They have been attracting very strong attention from the pharmaceutical industry for several years and are considered the next generation of therapeutic proteins. Although providing some solutions to the problems associated with mAbs, they do so only partially. The ambition of this thesis subject is to pave the way for the next generation, and the advent of new paradigms in the field of (bio)medicine. This collaborative project, funded by the ANR, intends to use synthetic chemistry, molecular biology and immunology approaches to generate Nbs derivatives which will have considerably improved biocompatibility (resistance to proteases, immunogenicity…) and will allow simple approaches for the controlled conjugation of probes and drugs. Our model targets are two different transmembrane proteins, LINGO1 and 5HT7R, due to their therapeutic interest, the lack of pharmacological tools to study them and the in-depth expertise of the group of Séverine Morisset-Lopez, partner of the ANR project, in the study of these targets.
The work of the doctoral student will be mainly devoted to the 'synthesis' aspect of this project, by implementing the chemical ligation methodologies developed by the host group to simplify the chemical synthesis of proteins.
Within the Center for Molecular Biophysics (CBM - UPR4301) located in Orléans on the CNRS campus, the doctoral student will carry out his or her activities within the thematic group "Synthetic proteins and bio-orthogonal chemistry". The CBM develops research at the interface of Chemistry, Biology and Physics which focuses on the molecular mechanisms of living organisms and the dysfunctions that lead to the development of certain diseases.
The doctoral student will be supervised by a CNRS researcher from this group and co-supervised by a post-doc working on the same theme. The thesis is funded by an French national research agency (ANR) program.
Constraints and risks
Applicants must send their CV and cover letter via the website emploi.cnrs.fr. Only applications received via this CNRS procedure will be considered.
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