Development of High-Titer Antidrug Antibodies in a Phase 1b/2a Infant Clesrovimab Trial Are Associated With RSV Exposure Beyond Day 150.

Abstract

Clesrovimab is a human half-life-extended monoclonal antibody in phase 3 evaluation for the prevention of respiratory syncytial virus (RSV) disease in infants. Antidrug antibodies (ADA) were observed at late time points in a phase 1b/2a study where clesrovimab was well tolerated with an extended half-life of approximately 45 days. Serum samples at days 150, 365, and 545 postdose were assayed for ADA titers. Samples with high ADA titers were characterized for their binding specificity to the Fab or the YTE portion of clesrovimab. RSV serum neutralization (SNA) titers were also measured on ADA-positive and ADA-negative infants. Additionally, a D25 (site Ø) competitive enzyme-linked immunosorbent assay (ELISA) was performed on ADA-positive available samples to determine RSV exposure. Local surveillance data was used to ascertain RSV circulation during the trial. High ADA titers were observed in a minority of infants at days 365 and 545 for all doses tested. Additionally, all high-titer ADA-positive infants had ADA directed towards the YTE epitope of clesrovimab. Moreover, these infants demonstrated robust RSV-SNA and had D25 competitive antibodies suggesting an RSV exposure after day 150, coinciding with the epidemiological data. RSV exposure in infants beyond day 150 after dosing is associated with ADA development and high RSV-SNA titers with no impact on pharmacokinetics. NCT03524118.