Glycoengineering by hyperglycosylation: a single approach to tailor biotherapeutic properties.

OGGERO, M. R.

Viña del Mar. Valparaíso

Conferencia; X Simposio Latinoamericano de Tecnología de Cultivo de Células Animales (X SLATCC); 2024

Pontificia Universidad Católica de Valparaíso. Universidad de Chile. Universidad de Concepción.

Sesión: Bioterapéuticos: desarrollo y control de calidad. https://www.pucv.cl/uuaa/x-slatcc/programa-programmeConferencia (Keynote de sesión): Glycoengineering by hyperglycosylation: A single approach to tailor biotherapeutic propertiesMarcos OggeroUNL, CONICET, FBCB, Centro Biotecnológico del Litoral, Santa Fe, Pcia. de Santa Fe, Argentina BioSynaptica SA, Santa Fe, Pcia. de Santa Fe, Argentinamoggero@fbcb.unl.edu.arProtein-based biotherapeutics have revolutionized the treatment of various diseases due to their remarkable specificity and strong affinity for their clinical targets. However, most proteins do not function as optimal drugs because their effectiveness is hindered by several intrinsic limitations related to their pharmacokinetic and/or pharmacodynamic characteristics. As a result, multiple strategies have been developed to extend the residence time of proteins, ensuring they reach therapeutic levels, while also enhancing other physicochemical and pharmacological attributes.Most proteins derived from eukaryotic cells undergo covalent modifications during or after their synthesis. This has led to the classification of these processes as co-translational and post-translational modifications. Among these, N- and O-glycosylation are the most prevalent and complex modifications that proteins can experience, influencing a variety of biological characteristics such as solubility, protease and thermal stability, immunogenicity, bioactivity, and pharmacokinetics. Consequently, glycosylation is one of the most critical features of many therapeutic proteins, determining their potency and efficacy. Moreover, the size and charge of proteins are significantly altered by glycans, making their modulation a powerful strategy to influence the pharmacokinetics and pharmacodynamics of biotherapeutics.In this summary, I present the work conducted in our lab using two iconic glycoproteins that were modified through glycoengineering by hyperglycosylation, a process that involves adding new glycans by introducing potential glycosylation sites. Through this approach, we produced potential biobetters and innovative compounds using animal cell cultures.One of the glycoproteins, interferon-α2b (cytokine that has antiproliferative, immunomodulatory, and antiviral properties) was N- or O-glycomodified to create hyper N-glycosylated or hyper O-glycosylated versions, improving its pharmacokinetic profile. The second glycoprotein, erythropoietin, was N-glycoengineered to inhibit its erythropoietic activity while maintaining its neurobiological function.Specifically, the N-glycoengineered erythropoietin led to the founding of a start-up and progressing to the national phase of patents. These actions represent key steps to move towards proof-of-concept trials, as well as preclinical and future clinical studies, paving the way for the development of a novel and effective biotherapeutic.