Immunogenicity and its impact in clinical trials

There is a shift in drug development field from the chemical compounds to the biological products - protein products and a shift from traditional pharmaceutical companies to biotechnology companies. For those who work on clinical trials on biological products, the term 'immunogenicity' must be a familiar term. Immunogenicity is the ability of a particular substance, such as an antigen or epitope, to provoke an immune response. In other words, if our drug is protein product, immunogenecity is the ability of the protein to induce humoral and/or cell-mediated immune responses. Immunogenicity testing is a way to determine whether patients are producing antibodies to biologics that can block the efficacy of the drugs. The development of anti-drug antibodies can also cause allergic or anaphylactic reactions, and/or induction of autoimmunity.

Several workshops have been organized to discuss the immunogenicity issues. Regulatory agencies are developing the guidelines to give industry the directions to incorporate the immunogenicity testing into the clinical development program for biological products.

Since the immunogenicity testing relies on the assay to measure the immune responses, the results of immunogenicity depend on which assay is used for testing. Therefore, the development of immunogenicity assay is also a critical issue in immunogenicity testing. Using an ultra sensitive assay could detect many false positives in immunogenicity testing. Using a less sensitive assay could under-estimate the immune response.

The following collection regarding immunogenicity testing should provide a good resource for this topic.

• EMEA's Guideline on Immunogenicity Assessment of Biotechnology-Derived Therapeutic Proteins
• A European Perspective on Immunogenicity Evaluation. Nature Biotechnology
• EMEA's Concept Paper on Immunogenicity Assessment of Monoclonal Antibodies Intended for In Vivo Clinical Use
• EMA: Immunogenicity Assessment of Monoclonal Antibodies Intended for In-vivo Clinical Use (2012)
• EMEA's Guideline on Immunogenicity Assessment of Biotechnology-Derived Therapeutic Proteins
• EMEA's Concept Paper on Guideline on Immunogenicity Assessment of Therapeutic Proteins
• Presentaton on 'EMEA guidance on immunogenicity for biologicals' by Dr. Robin Thorpe
• FDA's Guidance for Industry: Assay Development for Immunogenicity Testing of Therapeutic Proteins
• FDA Guidance: Immunogenicity Assessment for Therapeutic Protein Products
• Immunogenicity of Protein-based Therapeutics
• The immunogenicity of therapeutic proteins- what you don’t know can hurt YOU and the patient

If a company develops a follow-on biologicals, a generic form of biological product or a copycat of a biotechnology product, immunogenicity testing is typically one of the critical points that need to be addressed. The regulatory, therefore, issued the guidelines on the immunogenicity testing when developing the follow-on biologicals. 

• FDA/DIA Scientific Workshop on Follow-on Protein Pharmaceutials
• EMEA Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: one-clinical and clinical issues
• EMEA's Guideline on Comparability of Medicinal Products Containing Biotechnology-Derived Proteins as active substance: non-clinical and clinical issues