Modulating carbohydrate–protein interactions through glycoengineering of monoclonal antibodies to impact cancer physiology

Abstract

Diverse glycans on proteins help impact cell and organism physiology along with drug activity. Since many protein-based biotherapeutics are glycosylated and these glycans have biological activity, there is a desire to engineer glycosylation for recombinant protein-based biotherapeutics. Engineered glycosylation can impact the recombinant protein efficacy and also influence many cell pathways by first changing glycan-protein interactions and consequently modulating disease physiologies. However, its complexity is enormous. Due to recent advances in glycoengineering, modulating protein-glycan interactions become more amenable to therapeutic approaches. Here, we discuss how engineered glycans contribute to therapeutic monoclonal antibodies (mAbs) in the treatment of cancers, how these glycoengineered therapeutic mAbs affect the transformed phenotypes and downstream cell pathways, and how systems biology can help in the next generation mAb glycoengineering process by aiding in data analysis and guiding engineering efforts to tailor mAb glycan and ultimately drug efficacy, safety and affordability.

Glycans and glycosaminoglycans in neurobiology: key regulators of neuronal cell function and fate

“…GAG microarrays for the analysis of GAG-protein interactions [19][20][21] have also been applied to profiling the sulphation patterns of GAGs to determine growth factor interactive sequences [22,23] and have also identified CS-E tetrasaccharides motifs which act as TNF antagonists [24]. Development of clickECM cell-derived azide functionalised extracellular matrices (ECMs) [25], photoactivatable and chemoenzymatic glycan labelling tools [26][27][28], non-invasive two dimensional nuclear magnetic resonance spectroscopy [29], glycoengineering of monoclonal antibodies (MAbs) with improved carbohydrate-protein interactive properties and immune cell targeting capability has improved their efficacy in anti-cancer therapeutics [30]. Multimodal glycosylated conductive polymer biointerfaces suitable for the evaluation of carbohydrate-protein interactions [31] and nanoscale biomatrices for studies on glycocalyx interactions [32] have been developed.…”

Crystallizable Fragment Glycoengineering for Therapeutic Antibodies Development

“…For CDC, terminal galactose increases CDC by improving C1q binding, whereas terminal GlcNAc and sialic acid decrease CDC ( 12 ). Among these effects, reduction in fucose and terminal galactose, which improves ADCC and CDC, is highly desirable in antibody glycoengineering ( 76 ). Regulating α-2,6-linked terminal sialic acid is also an attractive strategy due to the anti-inflammatory role of these terminal sialic acid ( 77 ).…”

Awakening dormant glycosyltransferases in CHO cells with CRISPRa

“…For example, the bisecting N‐acetylglucosamine attached by Mgat3 (β‐1,4‐mannosyl‐glycoprotein 4‐β‐N‐acetylglucosaminyltransferase) and the alpha 2,6 sialic acid attached by St6gal1 (β‐galactoside α‐2,6‐sialyltransferase 1) are common on many human glycoproteins (Amann et al, ; Popp et al, ), but missing from proteins expressed in CHO cells. While the lack of these epitopes has not led to immunogenic responses (Butler & Spearman, ), these human epitopes may impact drug activity (Chiang et al, ; Reusch & Tejada, ; Tian et al, ). Fortunately, recent advances in gene editing tools and genomic understanding have increased our ability to manipulate CHO cells to overcome some of these shortcomings.…”

“…are common on many human glycoproteins (Amann et al, 2018;Popp et al, 2018), but missing from proteins expressed in CHO cells. While the lack of these epitopes has not led to immunogenic responses (Butler & Spearman, 2014), these human epitopes may impact drug activity (Chiang et al, 2016;Reusch & Tejada, 2015;Tian et al, 2019).…”