Descrizione del progetto
La modifica enzimatica degli anticorpi monoclonali per un’efficacia antitumorale superiore
Gli anticorpi monoclonali sono ingegnerizzati in laboratorio per imitare la capacità del sistema immunitario di difendersi da agenti patogeni dannosi, quali virus e cellule cancerose. Essi sono sempre più utilizzati con finalità terapeutiche e il mercato degli anticorpi ha registrato una crescita esplosiva negli ultimi anni. Gli anticorpi monoclonali sono in sostanza glicoproteine con componenti zuccherine legate a un sito particolare. Ciononostante, per raggiungere un’efficacia antitumorale superiore, devono essere caratterizzati da una struttura specifica e omogenea. L’obiettivo del progetto GlycoMabs, finanziato dall’UE, è quello di sviluppare un metodo per un’ingegnerizzazione precisa di anticorpi monoclonali avvalendosi di enzimi specifici. L’applicazione di una metodologia sintetica standardizzata di tal genere per i farmaci anticorpali dovrebbe incrementarne l’efficacia.
Obiettivo
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.
Campo scientifico
Programma(i)
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Meccanismo di finanziamento
MSCA-IF-EF-RI - RI – Reintegration panelCoordinatore
48160 DERIO VIZCAYA
Spagna