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

Abstract

Diverse glycans on proteins 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. Recent advances in glycoengineering now make it easier to modulate protein-glycan interactions. 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. Furthermore, we suggest 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.

Figure 1. Therapeutic mAb structure, glycoforms, and glycoengineering strategies for generating desired glycoforms

(A) The structure of an IgG with interaction-partner binding regions and N-linked glycosylation sites (highlighted in blue triangles) are annotated. (B) The dominant N-linked glycans on mAbs can vary depending on the host and product. However, (i) common glycans on therapeutic mAbs have been measured. (ii) MAbs expressed in heterologous expression systems introduce non-human compatible sugars and linkages, leading to immunogenicity and low serum half-life. (iii) Glycoengineering aims to make mAbs with N-glycans that are human compatible and exhibit enhanced mAb efficacy and safety. (C) Many glycoengineering efforts aim to enhance the drugs and achieve any of the three effects (i-iii) by modifying glycans on mAbs. NANA: N-glycolylneuraminic acid (hyper-sialylation). Data of (B) in this figure was adapted from [34].

Figure 2. Omics data and systems biology provide novel tools for rational glycoengineering of therapeutic mAbs and to assess the impact of glycoengineered mAbs on cancer

(A) Omics data can be acquired to identify how to glycoengineer mAb production cells. (B) Computational models of the pathways influencing glycosylation and protein production can serve as a platform for interpreting omics data and (C) guiding the rational design of glycans on therapeutic mAbs. (D) The impact of engineered mAbs on cancer physiology can further be analyzed using systems biology techniques, especially assessing the glycan-protein interactions [9].