La dimérisation des IgG humaines médiée par l'hème en tant que stratégie d'amélioration de leur activité fonctionnelle

Heme-mediated dimerization of human IgG as a strategy of enhancement of their functional activity

• Auteur / Autrice : Robin Lacombe
• Direction : Jordan Dimitrov
• Type : Projet de thèse
• Discipline(s) : Biologie moléculaire et cellulaire
• Date : Inscription en doctorat le 01/10/2022
• Etablissement(s) : Sorbonne université
• Ecole(s) doctorale(s) : École doctorale Physiologie, Physiopathologie et Thérapeutique (Paris ; 2000-....)
• Partenaire(s) de recherche : Laboratoire : Centre de recherche des Cordeliers (Paris ; 2007-....)
• Partenaire(s) de recherche : Equipe de recherche : Immunopathologie et immuno-intervention thérapeutique

Mots clés

Mots clés libres

Hème

Anticorps

Fonctions effectrices

Cancer

Pathogènes

Heme

Antibodies

Effector functions

Cancer

Pathogens

Résumé

Non relevant

The principal goal of the PhD project is to explore the feasibility of a cofactor-induced oligomerisation of IgG to potentiate the therapeutic efficacy of human anti-cancer antibodies and anti-viral antibodies. Our idea is based on two phenomena: Firstly, in our previous studies on the interaction of heme with therapeutic antibodies we found that the interaction of Trastuzumab with heme results in the formation of well-organized oligomers through Fab-Fab interactions of two IgG molecules. These species were considerably more potent in activating the complement system and inducing killing of cancer cells. Importantly, we were able to transfer the potential for oligomerisation mediated by heme on two unrelated monoclonal antibodies used in clinical practice, thus providing strong evidence of the feasibility of the engineering effort and the utility of its application for broad range of IgG molecules. Secondly, there is strong evidence in the literature about the ability of tumours (especially malignant) to provoke haemorrhages. Based on these two phenomena, we formulated our working hypothesis that the locally released heme and hemoproteins at tumour sites can be harnessed as trigger of oligomerization of engineered IgG molecules, thus increasing their pro-inflammatory and cytotoxic activities due to aggregation of the Fc portion in close proximity. This will result in higher antibody avidity, more efficient cross-linking of Fc-γ receptors, better recruitment of complement proteins (C1q) and, hence, a stronger activation of the immune effector cells and the classical pathway of complement system on the surface of cancer cells. On the other hand, increase in antibody avidity may provide a strategy to enhance the potency of certain pathogen-specific antibodies such as the broadly neutralizing HIV-1 antibodies. This is especially important as the spike on HIV-1 proteins are sparsely available and cannot be cross-linked by standard bivalent antibodies. Successful accomplishment of this project will have considerable impact due to clinical and social significance of cancer.