Immunogenicity issues in drug development.

Immunogenicity is an important factor that manufacturers must consider as they develop new protein therapeutics. It is important to understand the immunogenicity of new proteins both at the preclinical phase and in the clinical phase of development. This paper provides an overview of the issues that manufacturers should consider including some of the potential reasons that some proteins induce an immune response, a discussion regarding current methodology used to understand immunogenicity, and some examples of marketed protein therapeutics with immunogenicity issues. Given the increasing scrutiny from regulatory agencies around the way immunogenicity is assessed by manufacturers, the strategy of detecting and characterizing antibodies that are formed against protein therapeutics is becoming an important topic. Screening assays are typically performed first on all serum samples collected in the course of a trial to detect the presence of antibodies that can bind to the protein therapeutic. There are several platforms in use: radioimmune precipitation assays (RIP), enzyme linked immunosorbent assays (ELISA), electrochemiluminescent assays (ECL), and biosensor-based assays. Each has its advantages and disadvantages, and needs to be evaluated to identify the optimal platform for a specific therapeutic protein. Once antibodies are identified, a confirmatory assay is performed to verify and characterize the antibodies. A biological assay should be used next to test if these antibodies are capable of neutralizing the biological effect of the drug. Any sample that is positive for neutralizing antibodies, indicates that the antibody is probably having an impact on the patient's ability to derive full benefit from the therapeutic protein, and may be critical for patient safety.