Immunogenicity, why do we keep talking about it?  Immunogenicity can, in the simplest of terms, be described as a subject’s ability to generate antibodies specific to the dosed protein therapeutic.  While stating it this way understates the complexity of the immune system and the methods needed to detect and characterize the anti-drug antibody (ADA) response, it is, at the core, the question being asked.

Frequently, the ADA or immunogenicity assay development is an afterthought, as the primary focus on a project is to understand the absorption, distribution, metabolism, and excretion (ADME) of a dosed therapeutic.  Additionally, understanding the pharmacodynamics of the drug allows for investigators to make critical decisions regarding go/no-go check points early in a drug development program.  While these assays are important and provide great value to a development program, the ADA assay and the information gleaned from those analyses are equally important in the safety assessment and in developing a comprehensive view of the drug/subject interaction.

The reasons immunogenicity is needed and how it can impact a drug development program differs depending on where a drug candidate is in it’s life cycle.  The first instance where ADA may be needed are in the so-called “pivotal tox studies”.  These are the rodent and non-human primate studies that are performed following the FDA 21CFR part 58 (GLP) guidelines.  While the animals are being dosed with a human protein, and the emergence of ADA is not predictive of what will happen in humans, the effect ADA has on the PK parameters can be useful both in understanding the effect of an ADA response as well as providing an explanation for aberrant exposures or elimination profiles.  It is at this point (even if not non-clinical ADA assay is developed) that one should beginning activities to enable method development for the clinical studies.

Once an IND is filed and there are plans to dose humans, the need for an ADA becomes paramount.  Prior to filing the IND (at least 3 months prior) a surrogate antibody or positive control generation program should have been started.  The information that is obtained from the assessment of samples for ADA will help inform not only the PK, but the safety profile of the drug and determine if an antibody response is persistent (does not decrease once identified) or transient (can be dosed through without long-term adverse effects to drug exposure).  Additional evaluations can and are done to further inform the teams regarding the safety profile of therapeutic.  These evaluations determine the relative abundance of the ADA so a correlation can potentially be drawn to safety events and ADA prevalence, where on the protein (if a fusion protein) the ADA is binding, if the ADA is neutralizing and preventing the drug from binding the intended target or having the intended impact.

KCAS is a CRO that not only understands how to develop an ADA assay for your unique protein therapeutic, but can assist you in the development of an immunogenicity testing strategy.  Some of the services we offer regarding immunogenicity are method development and validation including a statistically robust method for determining a cut point for your assay that exceeds FDA expectations, resolving endogenous interferences, improving drug tolerance challenges, etc.  When your program is approaching the critical phase of development, call KCAS, we will ensure you have the best assays to enable the success of your therapeutic protein program.