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FDA researcher presents benchmark of Fc glycan profiles across 209 approved therapeutic antibodies
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Summary
Dr. Bao Lin Zhang presented an FDA benchmark showing that three glycoforms (G0F, G1F, G2F) dominate approved therapeutic antibodies and that sponsors set product‑specific, wide acceptance ranges; the analysis has implications for biosimilar assessment and product quality control.
Dr. Bao Lin Zhang, a senior biomedical research and product‑assessment expert at the U.S. Food and Drug Administration's Center for Drug Evaluation and Research, presented an FDA benchmark analysis of antibody glycosylation during FDA Grand Rounds. He said the team reviewed regulatory submissions, label databases and the antibody therapeutic product database with a cutoff of May 2025 to characterize glycan profiles across approved products.
"The first key takeaway message is Fc glycans are critical quality attributes of what we call CQA for therapeutic antibodies," Zhang said, describing how Fc glycan composition can influence effector functions such as antibody‑dependent cellular cytotoxicity (ADCC) and complement activation.
Zhang reported that as of May 2025 the FDA had approved 209 therapeutic antibodies. Most approvals remain classic monoclonal antibodies (about 71%), and approximately 81% of products are produced in Chinese hamster ovary (CHO) cells, with fewer products made in NS0 or SP2/0 mouse myeloma lines and a small number of nonglycosylated fragments produced in Escherichia coli. The top three glycoforms—G0F, G1F and G2F—together account for roughly 88% of glycoforms across products; the top 10 species represent more than 98% of observed glycans, Zhang said, while per‑product abundances can vary widely (for example, G0F ranged from about 20% to 90% across products).
Zhang emphasized that glycosylation is not template‑driven but depends on sequential enzymatic reactions and is highly sensitive to manufacturing variables (expression system, bioreactor conditions, purification and storage). As a result, sponsors establish product‑specific glycan specifications and acceptance ranges that can be broad: Zhang gave examples ranging from about 0.5–1.7% for a minor species up to 0–12% for total afucosylation in some products. "Specification is clearly product specific, and also the acceptance range are very broad," he said.
The presentation noted labeling language for certain approved antibodies often uses qualified phrasing about Fc‑mediated functions (for example, "in vitro," "possible mechanism"), and supporting evidence is commonly in‑vitro assay data rather than direct clinical validation. Zhang said these qualified mechanistic descriptions provide scientific context without implying additional clinical claims.
Zhang also described patterns among biosimilars: several biosimilars originally produced in NS0 or SP2/0 cell lines have been shifted to CHO expression to avoid nonhuman glycans such as α‑gal. He said the FDA review found that, for many biosimilars, the predominant glycan species mirror those of CHO‑produced reference products.
The benchmark analysis is slated to appear in an AAPS journal manuscript currently in press, Zhang said. He closed by reiterating that Fc glycan characterization and, when justified, functional bioassays (for example, FcγR binding, ADCC or CDC assays) together support science‑based regulatory decision making about antibody quality.
Next steps Zhang described include continued development of complementary analytical approaches and publication of the team's benchmark data to provide context for sponsors and reviewers.
