Bevacizumab is a humanized monoclonal antibody (mAb) targeting vascular endothelial growth factor (VEGF), which causes excessive growth of new blood vessels from pre-existing ones in the form of angiogenesis, underlying pathology of cancers and intraocular neovascular diseases. Through binding to soluble VEGF, bevacizumab sterically blocks the interaction of VEGF with VEGF receptor 2 on endothelial cells and thereby interrupts the activation of downstream signalling for angiogenesis. Bevacizumab is indicated for the treatment of a range of cancers, including metastatic colorectal cancer, metastatic breast cancer and non-small-cell lung cancer. It is also used for off-label treatment of eye diseases including neovascular age-related macular degeneration and diabetic macular oedema.
The patent expiration for protecting the originator product, Avastin, has prompted intense biosimilar development globally. The first two biosimilars, Mvasi (Amgen) and Zirabev (Pfizer) were authorized by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) between 2017 and 2019 [1, 2]. Since then, five other bevacizumab biosimilars have been approved in the European Union (EU) with many more potential biosimilars in late-stage clinical development worldwide [3].
Biosimilar mAbs produced from living cells tend to possess inherent variations in protein production. Furthermore, mAbs frequently undergo manufacturing changes, which can potentially alter critical quality attributes and impact safety and efficacy. Consequently, the World Health Organization (WHO) Expert Committee on Biological Standardization (ECBS) recognized the need for International Standards (IS) for VEGF antagonists and endorsed the development of these standards for harmonizing the bioactivity of these products [4].
In view of the above, the authors produced lyophilized bevacizumab preparations and conducted an international collaborative study with 25 participating laboratories from 11 countries [5]. The data showed that variability in relative potency estimates was reduced when the candidate standard was used compared to use of various in-house reference standards, enabling harmonization of bioactivity evaluation. The study demonstrated that the candidate standard [National Institute for Biological Standards and Control (NIBSC) code: 18/210] is suitable to serve as an IS for bevacizumab and it was therefore established by the WHO ECBS as the first WHO IS for bevacizumab with defined unitage for VEGF neutralization and VEGF binding activity. This IS coded 18/210 is intended for calibration of the manufacturer’s in-house standards as per regulatory guidance (ICH6QB) and national or pharmacopeial standards, allowing global harmonization of bioactivity assessment across different bevacizumab products. It will support manufacturers at various stages of product development and lifecycle management as well as during post-marketing surveillance, ensuring the safety and efficacy of bevacizumab biosimilars that offer the opportunity for more cost-efficient choices with increasing patient access to anti-VEGF therapies.
Conflict of interest
The authors of the research paper [5] declared that there was no conflict of interest.
Abstracted by Haiyan Jia, PhD, Principal Scientist, Head of Growth Factors, Division of Biotherapeutics, National Institute for Biological Standards and Control (NIBSC), A Centre of the Medicines and Healthcare products Regulatory Agency (MHRA), Hertfordshire, UK.
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Establishment of reference standards in biosimilar studies
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References
1. GaBI Online - Generics and Biosimilars Initiative. Biosimilars approved in the US [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2022 Jan 14]. Available from: www.gabionline.net/biosimilars/general/biosimilars-approved-in-the-US
2. GaBI Online - Generics and Biosimilars Initiative. Biosimilars approved in Europe [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2022 Jan 14]. Available from: www.gabionline.net/biosimilars/general/biosimilars-approved-in-europe
3. GaBI Online - Generics and Biosimilars Initiative. Biosimilars of bevacizumab [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2022 Jan 14]. Available from: www.gabionline.net/biosimilars/general/Biosimilars-of-bevacizumab
4. World Health Organization & WHO Expert Committee on Biological Standardization, sixty-seventh report. Proposed first WHO international standards for VEGF antagonists. WHO Technical Report Series. 2016;1004:52-3.
5. Jia H, Harikumar P, Atkinson E, Rigsby P, Wadhwa M. The first WHO international standard for harmonizing the biological activity of bevacizumab. Biomolecules. 2021;11(11):1610.
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