Abstract
Immunogenicity assessment during early stages of nonclinical biotherapeutic development is not always warranted. It is rarely predictive for clinical studies and evidence for the presence of anti-drug antibodies (ADAs) may be inferred from the pharmacokinetic (PK) profile. However, collecting and banking samples during the course of the study are prudent for confirmation and a deeper understanding of the impact on PK and safety. Biotherapeutic-specific ADA assays commonly developed can require considerable time and resources. In addition, the ADA assay may not be ready when needed if the study of PK and safety data triggers assay development. During early stages of drug development for antibody-drug conjugates (ADCs), there is the added complication of the potential inclusion of several molecular variants in a study, differing in the linker and/or drug components. To simplify analysis of ADAs at this stage, we developed plug-and-play generic approaches for both the assay format and the data analysis steps. Firstly, the assay format uses generic reagents to detect ADAs. Secondly, we propose a cut point methodology based on animal specific baseline variability instead of a population data approach. This assay showed good sensitivity, drug tolerance, and reproducibility across a variety of antibody-derived biotherapeutics without the need for optimization across molecules.
Highlights
All biotherapeutics, including antibody-drug conjugates (ADCs), have the potential to elicit an immune response in humans that could impact their efficacy, pharmacokinetics, and safety
We present a generic anti-drug antibodies (ADAs) assay format in cynomolgus monkey serum modified from the one described by Stubenrauch et al [13] to determine ADAs to ADCs
For our purpose, screening samples to determine if a positive response was produced after exposing the animals to the biotherapeutic and, if positive, a measure of the relative levels of ADAs were the key goals
Summary
All biotherapeutics, including antibody-drug conjugates (ADCs), have the potential to elicit an immune response in humans that could impact their efficacy, pharmacokinetics, and safety. Differences in background signal across molecules were observed in the pooled monkey serum and in earlier assay development experiments in serum from individuals. We explored the feasibility of adopting a floating population generic cut point with an earlier version of the assay using commercial samples from 30 cynomolgus monkeys. For this approach to work, the population background should not change in the presence of the added biotherapeutic. A different approach for estimating the cut point had to be followed
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