Glycosylation in Quality and Safety of Therapeutic Proteins

Recombinant therapeutic proteins, produced using recombinant DNA technology, constitute a major class of biologics. Over the past four decades, therapeutic proteins have proven to be safe and effective in the treatment of both inherited and acquired diseases, including cancers. Of the 414 FDA-approved recombinant therapeutic proteins (including biosimilars) — representing 275 active pharmaceutical ingredients (APIs) — 75% are glycoproteins produced from various expression systems. Glycosylation is frequently a critical quality attribute (CQA) for therapeutic glycoproteins due to its impact on key performance characteristics of the medicine: efficacy, pharmacokinetics and pharmacodynamics (PK/PD), targeted delivery, stability, safety, and immunogenicity. This article provides a high-level review of FDA-approved recombinant therapeutic proteins, glycosylation as a CQA, non-human glyco-epitopes, expression systems, glycoengineering strategies, regulatory and safety considerations, and perspectives on the development of biobetters with respect to glycosylation. Therapeutic topics in which glycosylation is relevant are also briefly discussed.