Titre de la dissertation: « Design of antibody-recruiting (macro)molecules by molecular modeling approaches ».

Promoteur: Monsieur Mathieu SURIN

Résumé de la dissertation: Antibody-recruiting molecules (ARM) are a promising class of molecules in the context of immunotherapy. By combining, a target-binding unit (TBU) to an antibody-binding unit (ABU), those molecules can fix the surface of a targeted cell (or an organism) and bind endogenous antibodies, already naturally present in the serum of every human being, in order to trigger an immune response against the disease. Recent studies make use of 2,4-dinitrophenyl (DNP) as an efficient ABU, while TBU can be designed to covalently bond labeled cells or to anchor lipid bilayer of cells through hydrophobic interactions. Multivalent ARMs, i.e. ARM containing multiple ABU and/or TBU, showed encouraging results to enhance the recruitment of antibodies on the targeted surface. However, the binding mechanisms of multivalent ARMs with antibodies is not currently fully clarified and need to be more closely examined in order to optimize the size, topology and number of functional groups of novel ARMs to enhance their therapeutic effects.In this context, this PhD thesis intends to use molecular modeling approaches to elucidate the 3D structures of ARMs to establish a relationship between the usual 2D representation and the 3D properties. Different families of ARMs are studied, from small molecules to linear and branched macromolecules. First, the study is focused on antibody recruiting small molecules (ARSM) containing one or two ABU or TBU. Molecular dynamics are used to characterize the conformations of those molecules and the effect of changing the number of functional groups or the nature of the linkers. MD is also used in association to molecular docking approaches to assess the binding modes of ARSM with the antigen binding fragment of an antibody.Secondly, the 3D structure of antibody-recruiting oligomers (ARO) are described. Those are sequence-defined molecules, a precisely synthesized class of macromolecules resulting in a unique defined structure, as opposed to classical polymers, characterized by a uniform chain sequence and polydispersity. In this case, the focal point is the description on how the position of ABU along the oligomeric sequence is translated into their accessibility in the 3D structure. A similar approach is used with antibody-recruiting branched oligomers (ARBO) where a ramification is brought to tune the topology for improved binding avidity. Finally, the accessibility of the functional units of antibody-recruiting dendrimers (ARD) is studied to describe the influence of a large number of ABU and TBU on the antibody recruitment.We systematically compare our results to experimental observations in terms of antibody binding avidity. Our molecular modeling approaches help to rationalize the effects of molecular structure on antibody binding and provide insights into the conformations, the accessibility of ABU, and the interactions between ARMs and antibodies.