The Mannose in the Mirror: A Reflection on the Pharmacokinetic Impact of High Mannose Glycans of Monoclonal Antibodies in Biosimilar Development

Biosimilar development has a well-documented foundation of product quality and extensive comparative analytics providing the bulk of the "totality of the evidence" that a proposed product is biosimilar to its reference product. This work provides a retrospective evaluation of a single critical quality attribute-high mannose glycans for monoclonal antibody biosimilars. Given the well-established conclusion that high mannose glycans can impact pharmacokinetic (PK) profile, we performed a retrospective evaluation of 21 monoclonal antibody biosimilar programs (those licensed before April 2022), their levels of glycans, and the methods used to study them. We provide herein a summary of the methods used and their relative performance. We also present a subset analysis for seven biosimilar products with levels of high mannose that differ from the corresponding reference product (and where other differences in quality attributes between the two that may influence PK profile were not observed or considered minor) and compared the PK profiles. Critically, this analysis has demonstrated that the measurement of glycan profiles is highly precise, reproducible within and across programs, and can detect differences in mannose levels, even those that do not impact PK. These results provide support that analytics rather than pharmacokinetic data may be sufficient to predict whether differences within a certain magnitude of this attribute are likely to impact PK. This work enhances the Agency's understanding of this issue allowing for better understanding of challenges faced by the biotechnology industry developing biosimilars.