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The National Institute for Biological Standards and Control

Confidence in biological medicines

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  • Cytokines and Growth factors

Cytokines and growth factors

Cytokines and growth factors signal through specific receptors, controlling the metabolism and function of all cell types in the body. They, along with products that modulate their activity, are used in treating a wide variety of pathological conditions. Their value as biomarkers for diagnosis and prognosis of diseases is increasing, along with their use in the production of other biological medicines. 

What we do

Our group aims to:

  • Establish WHO International standards (IS) and reference reagents for cytokines, growth factors and related proteins (e.g. monoclonal antibodies and fusion proteins) and work with pharmacopoieas towards provision of public standards
  • Develop reference standards for the immunogenicity evaluation of biotherapeutics 
  • Participate in EDQM activities via European Pharmacopoiea (Ph.Eur) expert groups and the Official Medicines Control Laboratories (OMCL) network
  • Conduct a diverse programme of research and development to support our standardisation and control work
  • Provide expert scientific advice on product testing and methods to pharmaceutical companies, regulatory agencies and contribute to policy-making in Europe (EMA) and at the global level (WHO)

Standardisation

WHO International Standards and Reference Reagents

The inclusion of WHO reference standards (where available) in bioassays is a regulatory requirement. The use of a single primary WHO standard to calibrate secondary/local standards, harmonises and reduces variability in results, across multiple laboratories. In some cases, the standards can also be used for other purposes such as calibration of immunoassays, including commercially available kits as per recommendations. For example, the infliximab and adalimumab international standard (IS) for bioactivity determination have also been recommended for use in therapeutic drug monitoring to facilitate a harmonised approach to clinical decision making.

We have established a diverse portfolio of over 80 reference standards comprising fusion proteins, derivatised proteins and biotherapeutic monoclonal antibodies. However, the need for bioactivity standards continues to increase due to:

  • the high number of novel therapeutics in development
  • the identification of cytokines as novel targets
  • intense activity in biosimilar medicines including monoclonal antibodies
  • their use as raw materials for advanced therapy products (as stated in the Ph.Eur)

Examples of standards in the pipeline are provided below:

Pipeline of monoclonal antibody (mAb) standards


Name
Target/Critical reagentAnticipated mAb standard
Status
Bevacizumab VEGF
2019/2020 New IS
Ustekinumab
P40 subunit of IL-12/IL-23

2021/2022 New IS


For some products, such as Bevacizumab, it is also important to standardise the target protein, VEGF, which serves as the critical reagent in bioassays. Some critical reagents for monoclonal antibodies are available as WHO reference standards from NIBSC and a program to deliver working standards for these has also been initiated.

To donate materials for reference standards or critical reagents (e.g. VEGF, IL-6, IL-23) or to participate in collaborative studies, contact enquiries@nibsc.org.

Reference standards and methods for immunogenicity evaluation

Treatment with a biotherapeutic often elicits formation of anti-drug antibodies (ADA) that can impact on clinical efficacy and patient treatment. ADA monitoring of patients for clinical decision-making is gaining momentum, however measuring ADAs is challenging and efforts to standardise such assays are recognised as an important step towards ensuring comparability of results. Our activities include:

  • standardising methods e.g., the MxA protein assay for neutralising antibodies for interferon-beta, a collaboration with industry and EMA 
  • assay development and provision of reference standards. The first WHO reference panel for monoclonal antibodies against erythropoietin (EPO) is now available in the catalogue. Details on this panel can be found in the Journal of immunological methods.

Efforts to develop antibody standards/panels for monoclonal antibody (mAb) therapeutics such as infliximab, adalimumab, rituximab are being planned.

To participate in collaborative studies, contact enquiries@nibsc.org.

Control

We assess the quality of products such as biosimilar medicines to support public health, by responding to incidents such as the TGN 1412 clinical trial and testing falsified medicines/counterfeits seized by MHRA’s enforcement group.

Find out more about NIBSC control testing. 

Research

Bioassay Development

Our expertise lies in developing novel or refining existing in vitro analytical assays and we have contributed to the development of assays for several cytokines and understanding adverse effects of biological medicines such as TGN1412.

Find out more from research published in British Journal of Pharmacology.

Recent work has focused on developing assays for mAb bioactivity. This includes antibody dependent cellular cytotoxicity (ADCC) assays using surrogate effector cells as opposed to traditional primary cell based assays. We characterised an assay using the B cell-line, Raji (target) and the surrogate CD16 expressing luciferase reporter cell-line, J9 (effector) containing an additional constitutively expressed reporter gene that allows for fluctuations in cell number and viability. We have applied this method to testing of rituximab products and the international collaborative study for this standard. 

Comparison of Mabthera with two rituximab similars

Mabthera (the innovator product) compared with two rituximab biosimilars (mAb 1, 2) in development using A: Surrogate ADCC assay and B: CDC assay. C: Data from N-glycan analysis of PNGase F released N-glycans including IgG from human serum as a standard for N-glycan species.

Immunogenicity

Testing for unwanted immunogenicity is a regulatory requirement for approval of biotherapeutic products. This includes validated anti-drug antibody (ADA) assays, since the impact of ADA on clinical outcome is critical. Our activities include:

  • Evaluation and development of ADA assays using different technologies e.g., ELISA, electrochemiluminescence (ECL), surface plasmon resonance; novel cell-based and non-cell-based (competitive ligand binding) assays
  • Application of the developed assays for assessing ADA and/or therapeutic in clinical samples and clinical significance
  • Understanding factors and mechanisms that contribute to immunogenicity. Find out more in our research published in Journal of Clinical Immunology, and Toxicology Sciences.

Fundamental biology

Since dysregulation of cytokines can result in disease pathology and progression, an understanding of the fundamental biology of these molecules is important in elucidating their role in disease settings. 

Our projects

Exploring the biology of IL-27 in human leukemic cells

We investigated the effect of IL-27 on the growth and survival of various human leukemic cell lines and on chemotherapy and showed new properties of IL-27 in tumour promotion and the inhibition of chemotherapeutic response. This suggests IL-27 as a potential therapeutic target for certain subtypes of human leukaemia. Find out more about this research in Journal of Interferon and Cytokine Research. 

Thrombotic microangiopathy and Interferon (IFN) therapy

IFN-α and IFN-β have been linked to thrombotic microangiopathy (TMA), a rare and life-threatening disorder affecting renal functions. To understand the molecular basis for the TMA in IFN treated patients, we investigated the in vitro effects of IFN on endothelial cell functions associated with angiogenesis and blood haemostasis. Results suggest that IFN interferes with angiogenesis and fibrinolysis through downregulation of urokinase-type plasminogen activator and upregulation of the potent inhibitor PAI-1 produced by vascular endothelial cells – this could potentially cause the loss of physiological endothelium thromboresistance and facilitate development of vascular complications in a clinical setting. This study was published in Thrombosis Research.

Co-culture model of angiogenesis

A co-culture model of angiogenesis, both IFN-α and IFN-β strongly inhibited VEGF-induced development of capillary-like structures in a manner comparable to avastin (bevacizumab, anti-VEGF monoclonal antibody).

Redox regulation of biotherapeutics

In inflammatory diseases and cancers, cells secrete thiol reductases (thioredoxin, TRX and protein disulfide isomerase, PDI) which can modify the disulfide bonding structure of extracellular proteins affecting function and signalling. Therapeutic mAbs have revolutionized the treatment of these diseases but many patients do not respond to treatment or develop ADAs which impacts on clinical efficacy. We are investigating whether TRX and PDI have a role to play in the reduced efficacy of such therapies.

Staff 

Dr Meenu Wadhwa, Section leader
Dr Clive Metcalfe
Dr Haiyan Jia
Dr Parvathy Harikumar
Dr Isabelle Cludts
Chris Bird
Dhyana Sharma (PhD student)
Sarah Frost (PhD student)
Kam Hua (PhD student)

Key publications (PDF, 49KB)

Selected standards

12/188: Pegylated G-CSF
17/132: Tumor Necrosis Factor -α
17/236: Adalimumab
16/170: Infliximab
13/204: Etanercept
02/286: VEGF

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