Immunogenicity of dupilumab in adult and pediatric patients with atopic dermatitis

• Published in: Frontiers in immunology Vol. 15
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Frontiers Media S.A 11-11-2024
• Subjects: ADA; anti-drug antibody; atopic dermatitis; dupilumab; immunogenicity; neutralizing antibody
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2024.1466372

BackgroundDevelopment of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs) to monoclonal antibodies may adversely impact pharmacokinetics, efficacy, and/or safety.ObjectiveTo describe incidence, titer, and persistence of dupilumab ADAs and NAbs, and their effects on pharmacokinetics, efficacy, and safety in patients with atopic dermatitis (AD).MethodsThis analysis included seven phase 3 randomized, placebo-controlled (N=2,992) and two long-term 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.ResultsTreatment-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 and -negative 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.ConclusionIn 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.Clinical trial registrationClinicalTrials.gov, identifiers (NCT02277743, NCT02277769, NCT02260986, NCT02395133, NCT01949311, NCT03054428, NCT03345914, NCT02612454, and NCT03346434).