Immunogenicity caused by biologicals, both originator and biosimilar, is an important issue that was raised by Dr Wadhwa from the National Institute for Biological Standards and Control.
Most biologicals induce immune responses (immunogenicity), in most cases these effects are harmless, but in some cases they can cause problems or even be fatal, such as in the case of pure red call aplasia.
Types of immunogenicity
Biological products can induce antibodies with different characteristics:
- non-neutralising (binding) antibodies against active (and inactive) product related substance(s)
- binding antibodies against contaminants
- neutralising antibodies
- mixtures of the above
- no antibodies.
Testing for unwanted immunogenicity
Testing for unwanted immunogenicity is therefore integral to product development (clinical and post-marketing phase) for ensuring the clinical safety of a biological, as well as product comparability when a biosimilar is developed.
In order to predict immunogenicity modelling algorithms, such as in silico and T cell, appear to be promising for identification of potential immunogenic T-cell epitopes, but information on the true clinical utility of these approaches in a prospective manner is lacking.
However, despite the promise of predictive testing, human clinical data is still needed for determining immunogenicity. This cannot be replaced by use of animal orin vitroor in silico tools.
The problem with unwanted immunogenicity is that it is impossible to predict the incidence, the characteristics of the immune response or the clinical consequences and significance of such immunogenicity. Clinical studies therefore have to be designed carefully and in such a way that these problems can be addressed.
Tiered approach to immunogenicity testing
A step-by-step approach can be used when approaching testing for unwanted immunogenicity. First using binding assays to screen products in order to identify all anti-therapeutic binding antibodies. Confirmatory assays can then be used in order to confirm antibodies. And finally neutralisation assays can be used in order to distinguish between neutralising and non-neutralising antibodies. Types of assays that can be used include:
- Binding antibody characteristics
- Binding assays – immunoassays
- Radioimmunoprecipitation assays (RIPA)
- Surface plasmon resonance (SPR)
- Immunoblotting
- Neutralising antibody characteristics
- Bioassays
Clinical studies
The immunogenicity of products needs to be compared, therefore studies need to be designed to demonstrate whether the immunogenicity of the products is the same or significantly different. This may affect the design of the studies and their interpretation. The consequences of any immunogenicity detected must also be compared.
Studies need to be carefully and prospectively designed to ensure all procedures are in place prior to initiation. This applies to all assays used in the trials. Procedures that need to be considered:
- Selection, assessment, characterisation and validation of assays
- Identification of appropriate sampling points, duration of testing
- Sample volumes and sample processing/storage
- Selection of statistical methods for analysis of data
Strategies also need to be established on a case-by-case basis, per product, per patient group and taking into account the expected clinical parameters. Strategies that need to be considered:
- In chronic use–sequential sampling for a year
- In view of variability of antibody responses, adequate numbers of patients needed
However, unwanted immunogenicity may occur at a level that is not detected in pre-approval studies, so assessment post-approval, as part of pharmacovigilance surveillance, is an important requirement.
Conflict of interest
The author declared that there is no real or apparent conflicts of interest to report. The views expressed by the author in the presentation are her own and do not represent her institution or any boards on which she has served.
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