"Rethinking Immunogenicity: An Integrated Approach Reveals the PK/PD Impact of Pre-existing and Drug-Sustaining ADA" Supplemental Materials-PK parameters Tables 1 and 2

Understanding how the immune system responds to biotherapeutic drugs is essential for predicting their safety and effectiveness. Some patients will develop anti-drug antibodies (ADA) that can change how a drug behaves in the body—altering its concentration (pharmacokinetics, or PK) or how it works (pharmacodynamics, or PD). Traditional immunogenicity assays often focus only on detecting ADA, then determining whether those antibodies neutralize the drug, which can miss important clinical effects. This study describes an example of a clinical investigation in which integrating ADA-sensitive PK and PD analyses provided deeper insight into how ADA influenced drug behavior. In a Phase 1 clinical study of DLX-2323, a single-chain antibody fragment (scFv), validation data revealed that some participants had pre-existing ADA that affected drug response over time. Further study demonstrated that the magnitude of ADA response directly correlated to lower drug clearance and smaller volume of distribution, providing a rare example of drug-sustaining ADA, a clinical impact that would not have been detected by a standalone neutralizing antibody assay. These findings show that combining ADA, PK, and PD data can reveal clinically meaningful effects earlier than standard neutralizing antibody assays alone. This integrated approach enables researchers to identify potential immunogenicity risks earlier, refine assay strategies, and enhance decision-making in drug development and clinical evaluation.