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

Abstract

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.

Keywords: RSV; antidrug antibodies (ADA); clesrovimab; passive immunization; serum neutralizing antibodies (SNA).

Figure 1.

Antidrug antibodies (ADA) targeting clesrovimab primarily target the YTE domain. A, Schematic describing the ADA characterization assay: ADA-positive infant sera were incubated with clesrovimab and either of the competing antibodies, RB1 (parental mAb to clesrovimab without YTE) and motavizumab engineered with YTE. Inhibition of clesrovimab binding in the presence of RB1, but not motavizumab-YTE would suggest that tested serum had ADA directed to the Fab portion of clesrovimab. Alternatively, inhibition of binding to clesrovimab in the presence of motavizumab-YTE but not RB1 would signify a YTE-specific ADA response. B, The chart shows data summarizing ADA specificity with 17/20 infants showing specificity to YTE, 1/20 infant to Fab portion, and 2/20 specific to both YTE and Fab portion of clesrovimab.

Figure 2.

SNA is higher in ADA-positive infants. A, RSV-SNA titers in clesrovimab (open circles) and placebo (open triangles) treated infants at screening, day 150, and day 365 time points. B, RSV-SNA titers in ADA-positive (open triangles) and ADA-negative (open circles) infants at screening, day 150, and day 365 time points, stratified by individual dose groups. C, RSV-SNA titers in ADA-positive (open triangles) and ADA-negative (open circles) infants at day 545 time point, stratified by pre- and full-term infants. The box is bounded by the 25th and 75th percentiles; the line within the box represents the median. The upper whisker extends from the upper hinge to the largest value no further than 1.5 × IQR from the hinge. The lower whisker extends from the lower hinge to the smallest value at most 1.5 × IQR of the hinge. D, Each point represents a paired SNA titer and serum clesrovimab concentration, of either ADA-positive (empty circles) or ADA-negative (closed triangles) infants at day 150 (dark blue) and day 365 (light blue) time points. Black line represents the fitted relationship between SNA titers and serum clesrovimab concentration. The shaded gray area represents the 99% prediction interval of the above fitted relationship. Abbreviations: ADA, antidrug antibodies; IQR, interquartile range; RSV, respiratory syncytial virus; SNA, serum neutralizing antibodies.

Figure 3.

ADA-positive infants with high SNA likely experienced second-season RSV exposure. A, Representation of RSV-positive cases in Florida, United States across time with overlay of dosing timelines until day 365 for infants A–G located at that clinical trial site. B, D25 (RSV site Ø) antibody competition at day 365. Nine of 11 infant sera (≥1000 ADA titers, closed circles) showed > LLOD signal in the AlphaLISA assay, detecting site Ø antibodies at day 365. Two of 11 infant sera that were below the LLOD (open circles) were imputed at LLOD value of 1.105 µg/mL for graphing purposes. Abbreviations: ADA, antidrug antibodies; LLOD, lower limit of detection; QR, quantifiable range; RSV, respiratory syncytial virus; SNA, serum neutralizing antibodies.

Figure 4.

Three clesrovimab-treated infants that were clinically diagnosed with RSV by PCR beyond day 150 are depicted. A–C, Each graph depicts 1 infant, showing the period of study (solid horizontal line) beginning with clesrovimab administration with time points day 365 and 545 after clesrovimab treatment: (A) infant A located in Colorado, United States, diagnosed with RSV at day 280; (B) infant B located in Seoul, South Korea, diagnosed with RSV at day 485; and (C) infant C located in Florida, United States, diagnosed with RSV at day 419. The RSV diagnosis along the time interval is depicted (vertical dotted line and relative day after clesrovimab administration). The curves depict the local RSV positive rate as reported by the respective public health RSV surveillance agencies. Abbreviations: PCR, polymerase chain reaction; RSV, respiratory syncytial virus.