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Updated: Jun 6, 2025
An Improved and High Throughput Respiratory Syncytial Virus RSV Micro-neutralization Assay
Published on: January 26, 2019
Development of High-Titer Antidrug Antibodies in a Phase 1b/2a Infant Clesrovimab Trial Are Associated With RSV
Nithya Thambi1, Jia Yao Phuah1, Ryan P Staupe1
1Department of Epidemiology.
Insights
Respiratory syncytial virus (RSV) exposure in infants after 150 days is linked to antidrug antibody (ADA) development. This association was observed with high RSV-neutralizing antibody titers but did not affect clesrovimab pharmacokinetics.
Area of Science:
- Immunology
- Pharmacology
- Virology
Background:
- Clesrovimab, a half-life-extended monoclonal antibody, is under evaluation for preventing respiratory syncytial virus (RSV) disease in infants.
- A phase 1b/2a study noted the development of antidrug antibodies (ADA) at later time points, despite clesrovimab being well-tolerated with a prolonged half-life of approximately 45 days.
Purpose of the Study:
- To investigate the characteristics and implications of antidrug antibody (ADA) development in infants receiving clesrovimab.
- To determine the relationship between ADA formation, RSV exposure, and neutralizing antibody responses.
Main Methods:
- Serum samples were analyzed for ADA titers at multiple time points post-dose (days 150, 365, 545).
- High-titer ADA samples were characterized for binding specificity (Fab or YTE epitope).
- RSV serum neutralization (SNA) titers and D25 competitive antibody levels were measured to assess RSV exposure and immune response.
Main Results:
- A subset of infants developed high ADA titers at later time points (days 365 and 545) across all tested doses.
- ADA in these infants were specifically directed against the YTE epitope of clesrovimab.
- Infants with high ADA titers also exhibited strong RSV-SNA and D25 competitive antibodies, indicating RSV exposure post-day 150.
Conclusions:
- RSV exposure in infants more than 150 days after clesrovimab administration is associated with ADA development.
- ADA development and high RSV-SNA titers were observed in conjunction with RSV exposure.
- The presence of ADA did not impact the pharmacokinetics of clesrovimab.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
RSV exposure in infants beyond day 150 after dosing is associated with ADA development and high RSV-SNA titers with no impact on pharmacokinetics.
Clinical Trials Registration:
NCT03524118.
