Keynote conference: Protein glycoengineering: towards novel biotherapeutics

OGGERO EBERHARDT, MARCOS

Cuernavaca, Morelos

Congreso; 7th Latin American Glycobiology Congress; 2023

Red de glicociencia en salud, Univ. Autónoma del Estado de Morelos (México), Centro de Investigación en Dinámica Celular

Protein-based biotherapeutics have transformed the treatment of several disorders due to their high specificity and affinity towards its clinical target. Unfortunately, most proteins do not perform as ideal drugs since their efficacy is compromised by numerous intrinsic limitations related to their pharmacokinetic and/or pharmacodynamic properties. Thus, many approaches have been developed aiming to improve the residence time of proteins in circulation to reach appropriate therapeutic doses, as well as to improve other physicochemical and pharmacological properties.Most eukaryotic cells-derived proteins undergo covalent modifications either during or after their synthesis. This creates the concept of co-translational and post-translational modifications (PTM). N- and O-glycosylation are the most abundant and complex PTM that proteins can undergo, affecting diverse biological properties, including solubility, protease and thermal stability, antigenicity, immunogenicity, bioactivity, and pharmacokinetics. Thus, glycosylation represents one of the most significant attributes of many therapeutic proteins, defining their potency and effectiveness. Also, both size and charge of proteins are completely modified by the presence of glycans, so that manipulation of this PTM represents a valuable tool to alter the pharmacokinetics and the pharmacodynamics of biotherapeutics. Herein, I summarize the work carried out in our lab using two iconic glycoproteins that were modified employing glycoengineering by hyperglycosylation, i.e., a procedure to add new glycosyl moieties by introducing potential glycosylation sites. In this sense, potential biobetters and innovators were produced using animal cell cultures. One of the glycoproteins, interferon-α2b -an antiproliferative, immunomodulatory and antiviral cytokine- was N-glycomodified or O-glycomodified to produce hyper N-glycosylated or hyper O-glycosylated versions of it with improved pharmacokinetic properties. The second glycoprotein was erythropoietin, that was N-glycoengineerized to block its erythropoietic function while preserving its neurobiological action.In particular the N-glycoengineerized erythropoietin led to the foundation of a start-up company and phases of patent nationalization as previous steps and essential milestones to move towards proof of concept tests, as well as preclinical and clinical assays to set up a novel and effective biotherapeutic.