Descripción del proyecto
Modificación enzimática de anticuerpos monoclonales para una mayor eficacia antineoplásica
Los anticuerpos monoclonales se diseñan en el laboratorio para imitar la capacidad del sistema inmunitario para combatir patógenos dañinos como, por ejemplo, virus o células cancerosas. Cada vez se emplean más con fines terapéuticos y el mercado de los anticuerpos ha experimentado un crecimiento asombroso en los últimos años. Los anticuerpos monoclonales son glicoproteínas con restos de hidratos de carbono unidos a un lugar concreto. Con todo, para lograr una mayor eficacia antineoplásica, deben presentar una estructura específica y homogénea. El objetivo del proyecto GlycoMabs, financiado con fondos europeos, es desarrollar un método para la ingeniería precisa de anticuerpos monoclonales con enzimas específicas. Se espera que la aplicación de esta metodología sintética normalizada para desarrollar anticuerpos terapéuticos mejore su eficacia.
Objetivo
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.
Ámbito científico
Programa(s)
Régimen de financiación
MSCA-IF-EF-RI - RI – Reintegration panelCoordinador
48160 DERIO VIZCAYA
España