Similar but not identical
A biosimilar is highly similar to, but not exactly the same as the existing, FDA-approved biologic, called the “reference” drug . People are familiar with generic versions of brand-name drugs, but biosimilars are not generic drugs. Generic versions of brand-name drugs are exact copies of chemically synthesized medicines. Biosimilars are not-quite-perfect copies of biologics – drugs derived from living cells that are impossible to replicate exactly.
Development of biosimilar proteins will present drug developers with a variety of challenges, both in manufacturing and in the clinic. Immunogenicity will prove to be one of the biggest challenges. Proper design and validation of an assay to detect anti-drug antibodies and accurate interpretation of sample analysis results will prove integral to developing a biosimilar protein.
Taking the above and below-mentioned into account Matriks Biotek® produced SHIKARI® Q-REMS and S-AIR as the first ELISA kits for the biosimilar of Infliximab, CT-P13 (Remsima®)and now also offers to develop custom ELISA kits for your biosimilars or biologics on contract manufacturing basis depending on the molecule provided. Matriks Biotek® is the first company to commercialize SHIKARI® ELISA kits for biological drug testing to measure trough levels and anti drug antibodies (immunogenicity) since 2008.
Comparisons for measuring especially ADA and trough levels are made by the tests developed for reference drug not for biosimilar which may differ on the test results. On the contrary we do not know the results when comparisons done by the ELISA kit developed for the biosimilar drug, it can present low immunogenicity as well.
The immunogenicity caused by the production of anti-drug antibodies (ADA) is also an important factor, and in many cases, an effect that prompts discontinuation of treatment. After long periods of treatment, ADA have been detected by the immunoenzymatic essay (ELISA). ADA may cause neutralization of the molecule, affecting PD and PK, making the treatment ineffective.
The causes of immunogenicity can be chimeric biological drugs (e.g. infliximab), even humanized molecules (e.g. adalimumab) and fully humanized biological drugs (golimumab)—most the cases the residual immunogenicity resides in the CDR regions —glycosylation profiles, fermentation, purification, formulation (aggregate formation), administration mode (i.m., i.v. and s.c.), dosing, degradation products and contaminants.
The pharmaceutical formulation strategy is a critical step and needs to be accurate. The knowledge about physical and biological properties of the biological drug orientate the formulation process. Important components of protein formulations are pH, stabilizer, solubilizer, buffer, and tonicity modifier (bulking agent). The typical stability problems observed in protein pharmaceuticals are non-covalent aggregation, covalent aggregation, deamidation, cyclic imide, and cleavages. This process can affect directly the efficacy (e.g. immunogenicity) and safety (e.g. adverse events) of a biological drug.
The potential immunogenicity of a therapeutic protein can be influenced not only by the manufacturing processes mentioned above, but also by the type of disease, route of administration and dose. Biosimilar proteins will most likely not be identical to the innovator drug, and because of this, immunogenicity becomes a major concern when developing biosimilar proteins. The potential exists for serious clinical consequences due to anti-drug immune responses with all protein therapeutics. A safe immunogenicity profile of the innovator product does not indicate that the biosimilar protein will be safe.
Proper immunogenicity assessment of biosimilars requires an in-depth understanding of the design of assays to detect anti-drug antibodies, implementation of proper validation procedures, and experience in analysis and interpretation of sample results. Use of an inappropriate anti-drug antibody assay format, improper validation testing or analysis of sample results may lead to misinterpretation of safety data. Anti-drug antibody assays must be properly designed and developed if they are to perform as intended. Many platforms and assay formats are available, and, depending on the protein therapeutic and its target, not all are appropriate for use. There are many variables that must be considered when developing an assay to detect anti-drug antibodies. The design of the clinical trial (single vs. multiple dose study), anticipated therapeutic drug levels in the immunogenicity samples, therapeutic target of the drug, mechanism of action of drug, and patient disease state all need to be considered when developing immunogenicity assays. Once the appropriate assay has been developed, the assay must be properly validated. Validation must include statistical determinations of both screening and confirmatory cut points. The use of arbitrarily set cut points to determine sample reactivity is improper and scientifically invalid. In order to ensure that the assay performs as expected when analyzing study samples, validation testing must also include assessment of signal precision, from which the in-study acceptance criteria can be generated. During sample analysis, data must be properly analyzed to ensure that the assay is performing as intended and that samples are not being reported as false negatives.
