Antibody-based therapies

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Table of contents

General Introduction
I Proteins in solution: from folding and stability issues to the design of synthetic chaperones
1 Protein folding and stability: to aggregate or not to aggregate?
1.1 Preamble: about the development of therapeutic antibodies and practical issues
1.2 Basic mechanisms leading to in vitro protein aggregation
1.3 Conventional strategies to limit in vitro protein aggregation
2 Towards the design of polymer-based and colloidal articial chaperones
2.1 In vivo folding and aggregation: role and mode of action of natural chaperones
2.2 En route to the design of articial chaperones
2.3 Amphiphilic polyelectrolyte as promising articial chaperones: protein binding, influence on conformational stability and on aggregation of proteins
2.4 Our project: study of model poly(sodium acrylate) derivatives as articial chaperones for antibodies and their derivatives
II Chemical refolding of proteins in the presence of amphiphilic polyelectrolytes
3 Renaturation of a model enzyme with amphiphilic poly(acrylate) chaperones
3.1 Bovine carbonic anhydrase B: a model enzyme to study aggregation during refolding
3.2 Keeping CAB soluble with poly(acrylate) derivatives
3.3 Polymers allow recovery of a native-like and active protein
3.4 Conclusion: discussion on the role of Coulomb and hydrophobic associations
4 Chemical refolding of scFv fragments with poly(acrylate) derivatives
4.1 Preamble: structure, use and folding of scFv
4.2 Size of scFv during refolding
4.3 Do polymers aect the secondary structure of scFv?
4.4 Conclusive remarks and perspectives
III Amphiphilic polyelectrolytes for the stabilization of IgG
5 Stabilization of IgG during thermal stress in the presence of poly(acrylate) derivatives
5.1 Motivation to study IgG stability
5.2 IgG:polymer complexes at room temperature
5.3 Evidence of association between polymers and heat-stressed IgG
5.4 Impact of poly(acrylate) derivatives on IgG aggregation upon thermal stress
5.5 Conclusion
Conclusion and perspectives
A Materials and methods
B Experimental techniques
C Supplementary data on CAB refolding assisted with PAA derivatives
D Supplementary data on scFv refolding assisted with PAA derivatives
E Supplementary data on thermally-induced IgG aggregation in the presence of PAA derivatives
Bibliography