AUTHOR=Kamal Mohamed A. , Kosloski Matthew P. , Lai Ching-Ha , Partridge Michael A. , Rajadhyaksha Manoj , Kanamaluru Vanaja , Bansal Ashish , Shabbir Arsalan , Shumel Brad , Ardeleanu Marius , Richards Susan M. , Yan Hong , Xu Christine R. , Rodríguez-Marco Ainara , Xiao Jing , Khokhar Faisal A. , Gherardi Guy , Babilonia Elisa , Maloney Jennifer , Mortensen Eric , Akinlade Bolanle , Braunstein Ned , Stahl Neil , Torri Albert , Davis John D. , DiCioccio A. Thomas 

TITLE=Immunogenicity of dupilumab in adult and pediatric patients with atopic dermatitis

JOURNAL=Frontiers in Immunology

VOLUME=Volume 15 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1466372

DOI=10.3389/fimmu.2024.1466372

ISSN=1664-3224

ABSTRACT=Background: Development of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs) to monoclonal antibodies may adversely impact pharmacokinetics, efficacy, and/or safety.Objective: To describe incidence, titer, and persistence of dupilumab ADAs and NAbs, and their effects on pharmacokinetics, efficacy, and safety in patients with atopic dermatitis (AD).Methods: This analysis included seven phase 3 randomized, placebo-controlled (N=2,992) and two longterm open-label extension (N=2,287) trials of subcutaneous dupilumab in adults and pediatric patients with moderate-to-severe AD. ADA, NAb, and dupilumab concentration in serum were assessed using validated immunoassays. ADA impacts on efficacy (EASI) and safety were assessed.Results: Treatment-emergent ADAs were observed in up to 8.6% (aged ≥18 years), 16.0% (12-17 years), 5.3% (6-11 years), and 2.0% (6 months to 5 years) dupilumab-treated patients. Among dupilumab-treated patients, ≤3.7% had persistent responses, <1% had high titers (≥10,000), and ≤5.1% were NAb-positive. NAbs were more common in patients with moderate-and high-titer ADA responses. High-titer ADAs, while infrequent, were the variable most associated with lower dupilumab concentrations in serum and loss of efficacy, independent of NAb status. Efficacy was generally similar in ADA-positive andnegative patients. For most patients with high-or moderate-titer ADAs, titers decreased and efficacy improved over time with continued dupilumab treatment. ADA-positive and -negative patients had similar incidences of treatment-emergent and serious treatment-emergent adverse events. One patient with high-titer ADAs developed serum sickness.In patients with AD, ADAs and NAbs had minimal impact on dupilumab concentration, efficacy, and safety, except for high-titer ADAs in a small number of patients.