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Thesis defence by Guillaume LEFEBVRE

Published on June 3, 2021
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PhD Defense July 2, 2021
8.45 am - Salle des Conseils Z 704
Building Z, 7th floor
Grenoble INP - Phelma
3 parvis Louis Néel - 38000 Grenoble
Accès : TRAM B arrêt Cité internationale
Free entrance - No registration

The protective effect of surfactants on monoclonal antibodies stability depends on material surface

Guillaume LEFBVRE

Guillaume LEFBVRE


Keywords:

Surfactants, Interfaces, Surface Plasmon Resonance imaging (SPRi), monoclonal antibodies (mAb), materials


cliquer pour voir la liste des membres du jury/clic here for the jury members


Abstract

During the production, purification, storage, transportation and delivery of monoclonal antibodies (mAbs), the stability of the drug is challenged in many ways, particularly by its exposure to diverse interfaces to which it can adsorb. Pharmaceutical industries address protein adsorption and aggregation issues during drug formulation optimization by adding surface-active excipients, such as polysorbate 80, polysorbate 20 and poloxamer. However, the precise mechanism(s) by which surfactants stabilize therapeutic proteins at interfaces is not well understood. There is a need to better understand adsorption of proteins and surfactants at interfaces and provide new screening methods to assess material compatibility of early drug candidates.

During my thesis, I have optimized an experimental Surface Plasmon Resonance imaging (SPRi)-based protocol to determine apparent adsorption rate constants of biomedically relevant molecules on bare surfaces in order to predict a drug/surface compatibility. We showed that mAbs have apparent adsorption rate constants for a model hydrophobic surface that are three orders of magnitude faster than the ones measured for commonly used polysorbates and poloxamer. We also showed, following the desorption kinetics of 3 different surfactants frequently used in pharmaceutical formulations, that, for Polysorbate 80 and 20, the desorption dynamic depends on surface occupancy whereas this is not the case for poloxamer.

We used SPRi, ELISA and Quartz Crystal Microbalance (QCM-d), as techniques to measure the absorption and desorption kinetics of mAbs and surfactants on a model hydrophobic surface (hexadecane SAM) and on polystyrene. We demonstrated a significant difference of the protective role of surfactants as a function of the material surface. We compared different materials frequently encountered during the production and storage of mAbs and demonstrated that, beyond hydrophobicity, the nature of the material surface affects the protective role of the surfactant. In a similar way, when comparing different classes of surfactants, we showed that the protective role of surfactants depends on their structure.

These results demonstrate that it is necessary to consider the material in formulation optimization. The protective role of surfactants is not by simple kinetic competition with the mAb on a hydrophobic surface and the nature of materials seems to play an important role. This thesis shows the importance of the material surface in drug stability.

Membres du jury/ Jury members :
 

Prof.

W.Friess

Ludwig-Maximilians-Universität München

Munich, Allemagne

Rapporteur

Directrice de recherche

K.Anselme

Institut de Science des Materiaux

de Mulhouse (IS2M)

Mulhouse, France

Rapporteur

Professeur associée

V.Massardier

Institut National des Sciences

Appliquées de Lyon (INSA)

Lyon, France

Examinateur

Chercheur CNRS

Y.Hou-Broutin

Systèmes Moléculaires et

nanoMatériaux pour l'Énergie et la Santé

Grenoble, France

Examinateur

PU-PH

V.Sautou

CHRU Clermont- Ferrand

Gabriel-Montpied

Clermont Ferrand, France

Examinateur

Ingénieur Docteur

T.Bourlard

Sanofi

Vitry sur Seine, France

Examinateur

Professeur

O.Gallet

Laboratoire ERRMECe

Neuville sur Oise, France

Examinateur

Professeur associée

M.Weidenhaupt

LMGP

Grenoble, France

Thesis Director


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Date of update June 28, 2021

Université Grenoble Alpes