Description du projet
Modification enzymatique des anticorps monoclonaux pour une meilleure efficacité anticancéreuse
Les anticorps monoclonaux sont conçus en laboratoire pour imiter la capacité du système immunitaire à combattre les agents pathogènes dangereux tels que les virus ou les cellules cancéreuses. Ils sont de plus en plus utilisés à des fins thérapeutiques, et le marché des anticorps a connu une croissance explosive au cours des dernières années. Les anticorps monoclonaux sont essentiellement des glycoprotéines dont les fragments de sucre sont fixés à un site particulier. Cependant, pour offrir une efficacité anticancéreuse supérieure, ils doivent présenter une structure spécifique et homogène. Le projet GlycoMabs, financé par l’UE, entend développer une méthode d’ingénierie précise des anticorps monoclonaux à l’aide d’enzymes spécifiques. La mise en œuvre d’une telle méthodologie de synthèse standardisée pour les anticorps devrait améliorer leur efficacité.
Objectif
Monoclonal Antibodies (mAbs) have gained an important place in the therapeutic arsenal of anticancer drugs. mAbs are glycoproteins containing a conserved N-linked glycosylation site at residue Asn297 of the fragment crystallisable (Fc). Most of the mAbs approved by the EMA are commercialized as a complex mixture of glycoforms at this site. It is well stablished that the precise chemical structure of the N-linked glycan modulates the effector functions mediated by the Fc domain. Specifically, for cancer treatment applications, the lack of fucose on the glycan structure contributes to enhance the effector functions of the antibodies, via increased affinity of IgG1 for FcgRIIIa on immune cells. New strategies to glycoengineering mAbs with homogenous glycoforms and lacking fucose core on their glycan structures have become a priority for the biopharmaceutical industry in order to obtain “biosuperior” anticancer drugs. Here, we will engineer a novel fucosidase enzyme that can act on fully glycosylated mAbs in order to simplify the chemoenzymatic synthesis of antibody drugs, based on the host laboratory expertise in Carbohydrate Active Enzymes. We will address three specific aims: (1) to define the structural basis of EndoS antibody specificity; (2) to elucidate the molecular mechanisms of IgG defucosylation by AlfC; and (3) to engineer an enzyme with fucosidase activity and specific for IgG. The GlycoMabs project will provide me an excellent and unique career opportunity by learning new skills in structural biology, protein engineering and project management which will grant me a leading independent position. Moreover, I will explore the industry interest in the application of our novel enzymes to generate homogeneous and afucosylated antibodies through an intersectoral secondment. Altogether, we will contribute to construct the next generation of therapeutic glycoengineered mAbs to tailor the immune reactions and increase their clinical potency.
Champ scientifique
Programme(s)
Régime de financement
MSCA-IF-EF-RI - RI – Reintegration panelCoordinateur
48160 DERIO VIZCAYA
Espagne