The US entered the era of biosimilars in 2015 with its very first US Food and Drug Administration (FDA) approved filgrastim biosimilar Zarxio (filgrastim-sndz) [1]. Since then, FDA has approved 11 more biosimilars [2]. Nevertheless, one concern with respect to the manufacturing of biosimilars is that every company has its own proprietary manufacturing process, which could potentially lead to differences in drug properties. Consequently, the debate on how ‘similar’ the biosimilar is to the originator still remains controversial. Thus, a comprehensive but rapid characterization platform that can validate any clinically meaningful differences is required. In this regard, Pisupati et al. [3] carried out a study comparing the reference product Remicade (infliximab) with the first US monoclonal antibody (mAb) biosimilar Remsima (Europe)/Inflectra (US) by incorporating state-of-the-art mass spectrometry-based multiple-attribute monitoring (MAM).
Infliximab is a chimeric mAb that was originally developed by Janssen in 1998. Decades later, its patent expired in the European Union in 2015 and in the US in 2018 [4]. Infliximab was designed to target tumour necrosis factor alpha (TNF-α) which is used for the treatment of a number of autoimmune diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease and ulcerative colitis. In rheumatic diseases, the Fab domain of infliximab is the most critical as it determines the efficacy of soluble TNF-α binding and neutralization. However, in inflammatory bowel disease (IBD), both the Fab and Fc domains play a critical role. The Fab domain determines the efficacy of trans-membrane TNF-α (tmTNF-α) binding, while the Fc domain establishes the efficacy of antibody-dependent cell-mediated cytotoxicity (ADCC) [5].
In recent study, Pisupati et al. investigated Remicade and Remsima using bottom-up, middle-down and intact mass spectrometry (MS). A study has shown high structural similarities in higher-order structure, sequence variants, oxidation and deamidation, but also illustrated the structural differences in the levels of C-terminal lysine truncation, soluble aggregation and glycation which have limited impact on the efficacy and the safety of the drug. However, the most significant differences observed between Remicade and Remsima were the distribution of glycoform and binding affinity of the Fc region to FcγRIIIa. There was a significant difference in the afucosylated glycan level in Remicade and Remsima displaying 19.7% and 13.2%, respectively. This difference led to 2-fold decreased binding affinity to FcγRIIIa in Remsima causing difference in the ADCC activity.
The authors therefore pointed to the importance of MS-based MAM. This method, they say, provides a robust but rapid framework of mAb characterization including various structural modifications and glycoforms that can affect the overall ADCC activity in mAb biosimilars. They added that ‘the ability to rapidly characterize and quantify complex mAb glycoforms will be especially critical for examining biosimilarity of oncology products that are reliant on an ADCC mechanism of action driven by afucosylation levels’. In addition, the method could also be used for characterization of post-approval originator product changes, resulting from process modifications, scale-up, and plant transfers.
Conflict of interest
The authors of the research paper [3] did not provide any conflict of interest statement.
Abstracted by Jukyung Kang, PhD Candidate, University of Michigan, Pharmaceutical Sciences, College of Pharmacy, Michigan, USA.
Editor’s comment
Readers interested to learn more about biosimilarity are invited to visit www.gabi-journal.net to view the following manuscripts published in GaBI Journal:
Demonstrating interchangeability and biosimilarity for US biosimilars
Supporting biosimilarity and extrapolation
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References
1. GaBI Online - Generics and Biosimilars Initiative. FDA approves its first biosimilar [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2018 Oct 26]. Available from: www.gabionline.net/Biosimilars/News/FDA-approves-its-first-biosimilar
2. GaBI Online - Generics and Biosimilars Initiative. Biosimilars approved in the US [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2018 Oct 26]. Available from: www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-the-US
3. Pisupati K, Tian Y, Okbazghi S, et al. A Multidimensional analytical comparison of Remicade and the biosimilar Remsima. Anal Chem. 2017;89(9):4838-46
4. Derbyshire M. Patent expiry dates for biologicals: 2017 update. Generics and Biosimilars Initiative Journal (GaBI Journal). 2018;7(1):29-34. doi:10.5639/gabij.2018.0701.007
5. Kang J, Pisupati K, Benet A, et al. Infliximab Biosimilars in the Age of Personalized Medicine. Trends Biotechnol 2018;36(10):987-92.
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