Project description
Enzymatic modification of monoclonal antibodies for superior anti-cancer efficacy
Monoclonal antibodies are engineered in the lab to mimic the immune system's ability to fight off harmful pathogens such as viruses or cancer cells. They are increasingly being used for therapeutic purposes, and the antibody market has seen an explosive growth over the last years. Monoclonal antibodies are essentially glycoproteins with sugar moieties attached to a particular site. However, for superior anti-cancer efficacy, they should present a specific and homogeneous structure. The scope of the EU-funded GlycoMabs project is to develop a method for the precise engineering of monoclonal antibodies using specific enzymes. Implementation of such a standardised synthetic methodology for antibody drugs is expected to enhance their efficacy.
Objective
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.
Fields of science
Programme(s)
Funding Scheme
MSCA-IF-EF-RI - RI – Reintegration panelCoordinator
48160 DERIO VIZCAYA
Spain