Impact of Repeated Antigen Exposure on Humoral Tolerance: Antidrug Antibodies After Single-Dose Versus Multi-dose Adalimumab

BACKGROUND: Therapeutic proteins such as adalimumab can elicit an antibody response. How dosing regimens impact immunogenicity remains ill-understood, especially with respect to the frequency of dosing. OBJECTIVE: We aimed to investigate the relationship between single versus multiple adalimumab doses and immunogenicity, in terms of anti-drug antibody production and skewing towards the non-inflammatory immunoglobulin G4 (IgG4) subclass. METHODS: Immunoglobulin M, immunoglobulin G, and IgG4 anti-drug antibodies were analyzed in retrospective cohorts of healthy individuals and patients with rheumatoid arthritis, psoriatic arthritis, spondyloarthritis, or psoriasis, receiving one or multiple doses of adalimumab, using optimized drug-tolerant assays, newly developed in the case of IgG4. RESULTS: A single dose of adalimumab proved highly immunogenic, while repeated dosing, resulting in prolonged exposure to high antigen concentrations, led to attenuation of the anti-drug antibody response. Immunoglobulin G4 anti-drug antibodies developed earlier than previously reported with drug-sensitive assays, appearing as early as week 3, even after a single dose of adalimumab. Skewing towards IgG4 was nevertheless stronger with repeated dosing. CONCLUSIONS: Repeated high-dose adalimumab exposure can limit both the magnitude and inflammatory potential of the antibody response. These results highlight drug exposure as a factor modulating the immunogenicity of biologics.