THESIS SUBJECT PROPOSAL

Vectorization of therapeutic antibodies for increased brain delivery and efficacy in Alzheimer’s disease

 

Team : BBB and Neuroinflammation

Thesis supervisor : Michel Khrestchatisky (DR1 CNRS)

State of the art

Alzheimer’s disease (AD) is the most common neurodegenerative disorder whose aetiology remains unknown. However, numerous studies highlighted the aggregation of Aβpeptides and hyperphosphorylated Tau protein that promote senile plaques and neurodegeneration. Recent Aβ immunotherapy showed efficacy for the first time in clinical trials, but one of the major drawbacks for the therapeutic antibodies (mAbs) is their limited access into the brain: very high doses of antibodies need to be administered to override the BBB with severe side effects. There is a strong need to improve mAb distribution into the CNS, in order to increase their efficacy and reduce side effects. The BBB & Neuroinflammation team and its partner (INP-Vect-Horus LabCom) have a solid experience in the development of vectors to transport biologics across the BBB (6 patent families, 75 patents worldwide).

Objective

Our main goal is to validate our most promising vectors by conjugating them to an anti-Aβ mAb, to determine vectorized mAb brain distribution and to assess therapeutic efficacy in a mouse model of AD.

Methods

Aim 1 -Genetic engineering and production of vector-mAb conjugates. Conjugates will be developed by combining several of our vectors with a prototypic anti-AβmAb developed for the clinic (mAb158, Bioarctic Neuroscience, humanized version BAN2401).

Aim 2 -Evaluation of BBB crossing in vitro and in vivo of vector-mAb conjugates. The conjugates will be tested on in vitro BBB models, the 5 most promising conjugates will be administered i.v. and their distributions will be analyzed. Pharmacokinetic studies will be performed using ELISA tests.

Aim 3 -Evaluation of vector-mAb conjugate efficacy in a mouse model of AD. The most promising conjugates (2 maximum) will be scaled-up to conduct a target engagement and efficacy study in the 5XFAD mouse model of AD. Free antibody and its vectorized versions will be administered i.v. weekly for 1 to 4 months to 5XFAD mice followed by histopathological analysis and behavioral tests.

Expected results

The proposed project will allow evaluation of the potential of different vectors to transport a therapeutic mAb into the brain and elicit efficacy. Following the proof of concept, the best vectors will be used further for brain delivery of different therapeutic antibodies, proteins or enzymes in different CNS diseases.

Candidate profile

The candidate is expected to develop skills in genetic engineering, in vitro and in vivo studies, and to evaluate the neurotherapeutic potential of drug candidates in an animal model of a major CNS disease.

Equipe de recherche: 
BBB and Neuroinflammation