Abstract Immunogenicity of monoclonal antibodies (mAbs) and other biotherapeutics remains a significant clinical challenge. The resulting anti-drug antibodies (ADAs) can neutralize the drug, accelerate its clearance, diminish efficacy, and potentially trigger hypersensitivity reactions via the formation of immune complexes (ICs). Current pharmacokinetic (PK) and ADA assays typically measure the drug or ADAs but provide limited information on IC structure, concentration, and duration of exposure in humans. While rat studies suggest larger ICs are rapidly cleared, human dynamics are less understood. This study investigated IC formation and clearance in patients enrolled in a terminated Phase 1 clinical trial of TYRP1-TCB, a novel T-cell engager. Analysis of patient samples revealed that six patients, treated with 0.4 mg every three weeks, developed ADAs, resulting in IC formation. These complexes were evaluated using size exclusion chromatography (SEC) and enzyme-linked immunosorbent assay (ELISA). ICs of diverse sizes were detected, with larger ICs cleared faster than smaller ones. These findings highlighted the need for appropriate PK assays in clinical studies. Total drug PK assays alone may overestimate drug exposure during an immune response, as they do not distinguish between binding competent and ADA-bound drug. In contrast, active drug assays do not give any information on circulating drug that can no longer bind to the target. Neither approach gives information on circulating ICs, which may represent the majority of the drug administered following a strong ADA response. This study underscores the importance of understanding ADA and IC dynamics for ensuring the safe and effective use of biotherapeutics. Graphical Abstract
Opolka-Hoffmann et al. (Fri,) studied this question.