Description du projet
Méthodologie avancée pour la production d’anticorps thérapeutiques
Les conjugués anticorps-médicament (ADC) sont des produits biopharmaceutiques qui emploient des molécules d’anticorps pour cibler spécifiquement des médicaments sur des cellules ou des tissus. Cependant, la structure complexe des anticorps empêche la conception et la production efficaces des ADC. Pour surmonter ce problème, les scientifiques du projet NSFTA, financé par l’UE, proposent de développer de nouvelles méthodes de synthèse pour contrôler le rapport médicament-anticorps et la modification des anticorps pour obtenir des structures d’ADC homogènes. Ces méthodes offrent également la possibilité d’obtenir des ADC avec de multiples charges utiles médicamenteuses ainsi que des anticorps à double spécificité, donnant lieu à de nouvelles interventions thérapeutiques.
Objectif
Antibody-Drug Conjugates (ADCs) are revolutionary next-generation therapeutics. The number of ADCs in the clinic is constantly growing with four of them having now reached the market. Despite this great promise, the complex structure of antibodies results in drawbacks for their reliable modification to construct ADCs, thus impairing the full potential of ADCs. One of the major reasons for clinical failure is that it is hard to control the drug to antibody ratio (DAR) to obtain homogeneous structures. Furthermore, current synthetic methods give access to ADCs with a DAR limited to values of 2, 4 and 8, thus lowering the variety of species being tested and possibilities to balance their toxicity. Hence, new synthetic methods giving access to homo- or hetero-functional ADCs with a high control of the DAR would be tremendous progress; being highly impactful to the ADC field and related patient outcomes. Here, we propose innovative methods to functionalise antibodies. Based on a well-established, patented disulfide bond re-bridging method, and orthogonal click ligations, we will finely control antibody modification. This will yield: 1) Mono-functional ADCs with highly controlled DAR, including odd DARs (DAR 1, DAR 3...). This is fundamental to determine the optimal ratio between drug loading and hydrophobicity to obtain the best therapeutic activity. 2) Hetero-functional ADCs with controlled amount and site of functionalisation with different payloads. This includes production of DAR 1+1, DAR 1+1+1…several combinations of payloads are possible, paving the way to promising multi-therapies. 3) Fully synthetic bi-specific antibodies. Our method provides an unprecedented way to obtain bi-specific antibodies in a controlled and adaptable fashion from native antibodies, i.e. without requiring bioengineering. The project addresses unmet needs in the therapeutic antibody field and could bring unprecedented outlooks to this booming sector.
Mots‑clés
Programme(s)
Appel à propositions
(s’ouvre dans une nouvelle fenêtre) H2020-MSCA-IF-2018
Voir d’autres projets de cet appelRégime de financement
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
WC1E 6BT London
Royaume-Uni