Monoclonal antibodies have revolutionised the treatment of a variety of diseases including cancer, inflammation, autoimmune conditions and infectious diseases. In recent years, the global market has expanded as patents for early ‘blockbuster’ monoclonal antibodies expire, paving the way for the development of more cost-effective biosimilar drugs.
As they are large and highly complex molecules made in living cells, monoclonal antibodies are very sensitive to differences in manufacturing processes. Therefore, to gain regulatory approval, biosimilars are subjected to a rigorous comparability exercise, involving measurements of bioactivity, in order to demonstrate similarity to a licensed originator product.
The WHO has acknowledged a global need for reference standards that can be used to calibrate in-house assays and harmonise bioactivity assessment of monoclonal antibody products throughout their life cycle. As a world leader in biological standardisation, the NIBSC has committed to develop a range of products to address this unmet need.The WHO has acknowledged a global need for reference standards that can be used to calibrate in-house assays and harmonise bioactivity assessment of monoclonal antibody products throughout their life cycle. As a world leader in biological standardisation, the NIBSC has committed to develop a range of products to address this unmet need.
Bevacizumab, initially sold under the brand name Avastin®, is an effective treatment for a range of cancers, such as colorectal cancer, breast cancer and lung cancer, and is included on the WHO Model List of Essential Medicines. It prevents the pathological growth of new blood vessels by inhibiting the effects of a molecule known as vascular endothelial growth factor (VEGF). There are currently four bevacizumab biosimilars authorised for use in Europe and five have received positive opinion from the European Medicines Agency. Several other products are in late stage clinical development.
The International Standard for Bevacizumab (NIBSC code: 18/210) was established by the WHO ECBS following an international collaborative study led by the NIBSC and involving 25 participants. The purpose of the study was to evaluate the standard’s suitability as a reference material and to assign values for its biological activity in International Units. The standard was assessed for its VEGF neutralizing and VEGF binding activity in a range of cell-based bioassays and direct binding assays. Crucially, the results indicated that the use of this standard reduced the variability of bioactivity measurements when compared with participants’ in-house reference standards.
Dr Haiyan Jia, Head of Growth Factors in the Division of Biotherapeutics at the NIBSC, comments:
“The availability of this standard will enable global harmonisation of the potency assessment of Bevacizumab bioactivity. It will support manufacturers during product development and assist regulatory decision-making as well as post-marketing surveillance, ensuring that patients have access to Bevacizumab products that are consistent in safety, quality and efficacy.”
Trastuzumab, known by the brand name Herceptin® among others, significantly improves survival in patients with certain types of breast or gastric cancer, and is also featured on the WHO Model List of Essential Medicines. It works by blocking the signalling of human epidermal growth factor receptor 2 (HER2) to slow tumour growth as well as by engaging cells from the immune system into killing tumour cells. A total of six biosimilars for trastuzumab have been approved following patent expiry and approximately thirty are believed to be under development.
As for Bevacizumab, the International Standard for Trastuzumab (NIBSC code: 19/108) was also evaluated in a multi-centre collaborative study to assess its suitability and to assign international units of bioactivity. Data showed that the standard harmonised the reporting of Trastuzumab bioactivity as measured with a range of in-house assays used by 25 participating laboratories. These include cell-based assays for inhibition of proliferation (IOP) activity and antibody dependent cell mediated cytotoxic activity (ADCC). The standard was also useful in antibody dependent cell mediated phagocytosis (ADCP), and cell-based and non-cell based HER2 and FcγRIIIa binding assays.
Dr Sandra Prior, Senior Scientist in the Division of Biotherapeutics at the NIBSC, adds:
“As more biosimilar monoclonal antibody products are approved and in development, the need for international standards is becoming increasingly evident. This preparation will facilitate the traceability of multiple biological activities across Trastuzumab products and help to ensure the consistency of the treatments that patients receive.”
To find out more about the importance of International Standards for the monoclonal antibody field, read our latest article published in Nature Biotechnology.
The development of these two reference materials is part of a broader programme of work by the NIBSC to support the standardisation of monoclonal antibodies and increase patient access to these life-saving therapies.
They follow the establishment of WHO International Standards for Rituximab (NIBSC code: 14/210), Infliximab (NIBSC code: 16/170) and Adalimumab (NIBSC code: 17/236), which are now available for use by manufacturers, regulators and pharmacopoeias globally. International standards for Cetuximab and Ustekinumabare also currently under development at the NIBSC, with further products in the pipeline.
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