Immuno-Oncology BioA: Pre-Existing ADAs Affecting PK
When administering human monoclonal antibodies, reconstituted human proteins, and antibody drug conjugates (ADCs), anti-drug antibodies (ADAs) can form and affect the Biotherapeutic’s exposure, bioavailability, and pharmacodynamic effects. The qualities of these ADAs – such as their specificity, magnitude, timing, maturity, and affinity – can impact pharmacokinetics (PK) and pharmacodynamics (PD).
Challenges Presented by ADAs in Animal Studies
It is evident that the current regulatory guidelines for immunogenicity assessments used in clinical trials are not being applied uniformly in non-clinical studies. The determination of ADAs in animal studies is not a dependable predictor of the immunological response in humans. According to the ICH S6 addendum, immunogenicity should be thoroughly investigated if there is any indication of:
- Altered pharmacodynamic or pharmacokinetic activity
- Unexpected changes in exposure without a pharmacodynamic marker
- Any signs of immune-mediated reactions
The European Biological Forum (EBF) recommends simplifying non-Clinical ADA assessments based on the likelihood of immune response in each animal species. However, ADA samples should be banked regardless of whether they will be assessed, following ICH S6(R1) guidelines.
It is also important to determine the ADA amounts in animal species prior to dosing them with a Therapeutic. Understanding the pre-existing ADA amounts will offer a more accurate toxilogical concentration of the Therapeutic. Without this understanding, the Therapeutic concentration will be artificially reduced, which can effect the toxilogical response.
Pre-Existing ADAs and Their Effect on the PK Curve
Testing for High, medium, or low pre-existing ADAs to the biotherapeutic in the pre-dose animal species should be done before dosing for the toxicological study. This assessment will help in the risk assessment of the PK/PD curves, as described in Impact of Anti-Drug Antibodies in Preclinical Pharmacokinetic Assessment, by Theingi M. Thway1. The Paper explains that existing ADAs to in the per-dose serum will affect the PK and PD curve once the biotherapeutic is dosed over time. The data shows that the PK curve will drastically decrease with the increase of pre-existing concentrations of ADA. Without determining this pre-existing concentration of ADAs, and selecting animals with minimal amounts of ADA, the PK and PD values from these animals will vary greatly.
Sword Bio’s Approach to PK/PD Studies: Pre-Dose ADA Assays
Sword Bio will assess the pre-existing serum levels of ADAs for toxicological animal PK/PD studies if the client sends us the pre-dose samples. This is an important service that can help our clients with very difficult PK/PD data and help in the ultimate goal of getting their biotherapeutic into the Clinic.
If you have any questions about how this additional tool in Sword Bio might be able to help you with your project, please connect with a member of our team!
- Theingi M. Thway, Ivan Magana, Ami Bautista, Vibha Jawa, Wen Gu, and Mark Ma; Impact of Anti-Drug Antibodies in Preclinical Pharmacokinetic Assessment, The AAPS Journal, Vol. 15, No. 3, July 2013 (# 2013)