Development of a New Generation of Antibody-drug - Tours, France - Université de Tours

Université de Tours

Entreprise vérifiée

Tours, France

il y a 2 semaines

Posté par:

Sophie Dupont

beBee Recruiter

Description

DEVELOPMENT OF A NEW GENERATION OF ANTIBODY-DRUG CONJUGATES:

Réf
ABG-120613
Sujet de Thèse 23/02/2024
Autre financement public
Université de Tours
Lieu de travail
Tours
Centre Val de Loire
France
Intitulé du sujet
DEVELOPMENT OF A NEW GENERATION OF ANTIBODY-DRUG CONJUGATES
Champs scientifiques
Chimie
Biotechnologie
Santé, médecine humaine, vétérinaire
Mots clés bioconjugation, chemical biology, proteolytic cleavage, cathepsins, metastasis, cancer, therapeutic chemistry, organic chemistry
Description du sujet:

Offer type:
PhD thesis

Financing:
ANR / FRANCE 2030

Salary range: 1747 € monthly net income

PROJECT:

Pulmonary metastasis are associated with a neutrophilic and macrophagic inflammation, leading to the secretion of proteases like human neutrophile elastase (HNE) and cathepsins (B, K, L) in the tumor microenvironment.

These overexpressed proteases can be used as tools to activate the release mechanism of antibody-drug conjugates (ADCs).

ADCs combine a highly potent cytotoxic agent (drug or payload) conjugated onto a monoclonal antibody (mAb) directed to a tumor-selective antigen, through a suitably constructed linker, and are designed for the selective delivery of the drug to the tumor site.

The objectives of this project is to use neutrophilic inflammation (HNE, cathepsins) to release a potent cytotoxic agent into the inflammatory microenvironment of lung metastases, using a suitably designed ADC containing a protease-sensitive linker.

In a previous work, we developed a neutrophile elastase-sensitive ADC targeting HER2 as a proof of concept. This know-how will be used to develop new protease-sensitive linkers in this study. Different payloads (_e.g_. auristatin or camptothecin derivatives) and bioconjugation technologies will also be tested.

This project is divided in several tasks: (1) synthesis of drug-linker and bioconjugation onto mAbs to produce new immunoconjugates; (2) analysis and characterization of prepared immunoconjugates: physico-chemical properties, (3) _in vitro_ evaluation of proteolytic cleavage (4) _in vitro_ characterization of antigen binding affinity and immunoconjugates internalization into antigen-positive cells (collaboration with NMNS EA6295, Tours); (4) _in vitro_ evaluation of immunoconjugates cytotoxicity on several human cancer cell lines (collaboration with NMNS and IRCM teams, U1194 INSERM, Montpellier); (5) _in vivo_ studies on different murine models (collaboration with IMOST, UMR1240 INSERM, Clermont-Ferrand).

This project is attached to high-priority programmes dedicated to therapeutic biodrugs and antibodies (ARD CVL Biomédicaments, APR IR, Labex MabImprove, Cancéropôle Grand Ouest).

For this new project, the recruited PhD student will be helped and will work in synergy with a post-doc expert in the field, 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.

Prise de fonction:

01/10/2024
Nature du financement:
Autre financement public

Précisions sur le financement:

ANR
FRANCE 2030
Présentation établissement et labo d'accueil:
Université de Tours

Recruiting organization: University of Tours

UMR1100 INSERM UT - CEPR, Team 2 "Proteolytic Mechanisms in Inflammation", group "Immunoconjugates" (C. Denevault, N. Joubert)

Workplace:

TOURS FRANCE

Site web:

Intitulé du doctorat: