A fairly common event with therapeutic proteins is the generation of immune responses to the therapy or related proteins by the patient’s immune system. These immune responses have the potential to affect product pharmacokinetics, pharmacodynamics, safety, and efficacy. Their high variability, ranging from no detectable effect to an extremely harmful effect, makes detection of immune response in clinical trials important (see the guidance “Immunogenicity Assessment for Therapeutic Protein Products” for more details). Tests for anti-drug antibodies (ADA) are the most common means of monitoring dose-related immune response, and the FDA released a final guidance on the development and validation of such tests in January 2019.

The assay development guidance describes appropriate design elements, development and validation strategies, and implementation of ADA tests for various clinical purposes including screening, confirmation, titration, and neutralization. The guidance is based on the best available immunoassay science; however, its important to note that all immunoassays have limitations to their sensitivity (the lowest level of antibody that can be detected) and specificity (the test may produce a positive result for non-ADA proteins). Immunoassays are relatively inexpensive and simple to run (once validated), so they are likely to continue as primary safety endpoints for clinical trials. In the future I’d like to see some assay development work on mass spectrometry assays for such proteins, as this detection technique is both more sensitive and selective and can be coupled with separation techniques to isolate the ADA from the other proteins in the sample.

Text Copyright © 2019 Katrina Rogers