Afucosylated biosimilars: the path to matching interrelated critical quality attributes

Biosimilars/Research | Posted 20/04/2018 post-comment0 Post your comment

Advances in analytical characterization and increased understanding of drug mechanisms of action have resulted in the ability to raise the quality and safety of biosimilars by introducing critical quality attributes (CQA), which must be preserved during the manufacturing process. However, to realize these benefits, biosimilars manufacturers must develop the means to ensure these CQAs are met. For afucosylated IgG1s that rely on afucosylation content for efficacy, this has been challenging, since precisely matching both afucosylation content and biological activity has proven to be extremely difficult. In a recent paper, Chung and Zhan [1] elaborate on the underlying basis of these difficulties and highlight the work of several groups that has opened a path to directly addressing this problem.


Several major considerations underlie the difficulty associated with precisely matching both afucosylation content and biological activity. First, both attributes reflect averages taken over a heterogeneous population, so that samples with similar afucosylation content or activity can be very different at the molecular level. It is well known that four major classes of afucosylated glycans, GO-F, G1-F, G2-F and high mannose, contribute to measured afucosylation content.

However, a more involved complication that is generally overlooked is the fact that afucosylation content and biological activity are not independent quality attributes. Afucosylation enhances biological activity, and this enhancement is affected by the nature of the class of afucosylated Fc glycan and how these Fc glycans are distributed among the IgG1 backbone. As such, samples with similar afucosylation content can have very different biological activity, and vice versa. The latter is particularly relevant to biosimilars with low afucosylation content, in which fucosylated Fc glycans make significant contributions to activity. Accordingly, measurements of biological activity that do not properly account for the contributions to activity of the major Fc glycans fail to adequately identify the source of the biological activity. The importance of directly relating biochemical activity to afucosylation content cannot be overstated, since measurements of both activity and afucosylation are method dependent.

Chung and Zhan discuss these considerations and highlight recent advances by several groups that now provide a means to directly address these considerations. The experimental tools needed to implement afucosylation-specific assays are now in existence. Additionally, a mathematical justification for these assays based on classical biochemical mechanisms has been provided so that the means for dissecting activity into its component contributions now exist. These developments provide the ability to directly address the complications associated with matching multiple interrelated CQA that have hitherto hindered the development of therapeutic afucosylated biosimilars.

Conflict of interest
The author of the research paper [1] declared that there was no conflict of interest.

Abstracted by John D Chung, Bioengineering Consulting and Department of Chemistry, Mendocino College, USA.

Related articles
Stakeholders comment on FDA’s draft statistical biosimilarity guidance

FDA issues draft guidance on statistical approaches to evaluating similarity for biosimilars

Quality attribute changes for rituximab

1. Chung JD, Zhan PL. Afucosylated biosimilars need afucosylation specific assays. MOJ Cell Sci Rep.  2017;4(5): 00101. doi:10.15406/mojcsr.2017.04.00101

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

Copyright – Unless otherwise stated all contents of this website are © 2018 Pro Pharma Communications International. All Rights Reserved.

comment icon Comments (0)
Post your comment
Most viewed articles
About GaBI
Home/About GaBI Posted 06/08/2009
EU guidelines for biosimilars
EMA logo 1 V13C15
Home/Guidelines Posted 08/10/2010